Synthesis of heterocyclic compounds by ring-closing metathesis (RCM): Preparation of oxygenated or nitrogenated compounds

Article abstract of DOI:10.1055/s-2006-942360

Novel methods for heterocyclic synthesis by metathesis have been developed. Versatile heterocyclic compounds were easily prepared in good yield from intermediate olefins by ring-closing olefin metathesis using the catalyst dichloro(benzylidene)bis(tricycl

Full text of DOI:10.1055/s-2006-942360

PAPER
1823
Synthesis of Heterocyclic Compounds by Ring-Closing Metathesis (RCM):
Preparation of Oxygenated or Nitrogenated Compounds
S
ynthesi
s
s
of
H
eter
a
ocyclics by
bRCM el Sánchez, Maria Dolors Pujol*
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643,
08028 Barcelona, Spain
Fax +34(93)4035941; E-mail: mdpujol@ub.edu
Received 16 November 2005; revised 13 January 2006
furnish the desired heterocyclic systems. We found that
Abstract: Novel methods for heterocyclic synthesis by metathesis
these dienes require vigorous conditions for ring closure.
Among the various solvents (benzene, toluene and dichlo-
romethane) and conditions tested, we found that benzene
at 60 °C gave the best results (see Schemes 1– 4).
have been developed. Versatile heterocyclic compounds were easi-
ly prepared in good yield from intermediate olefins by ring-closing
olefin metathesis using the catalyst dichloro(benzylidene)bis(tricy-
clohexylphosphine)ruthenium.
Key words: ruthenium catalysts, ring-closing, olefin metathesis,
heterocyclic systems
Initially we chose to synthesize nine-membered diazaben-
zo-fused heterocyclic compounds starting from the readi-
ly available bis-allyl compound 4. The amine 1 was
obtained from commercially available 2-nitrobenzyl chlo-
ride and benzylamine by conventional alkylation proto-
cols.6 Compound 1 was then converted into the
nitrocarbamate 2, by acylation using ethyl chloroformate
according to established procedures.7 Treatment of 2 with
H2/Pd-C yielded the reduced and debenzylated intermedi-
ate which afforded the bis-carbamate 3 after acylation
with ethyl chloroformate. The resultant bis-carbamate 3
was then alkylated with allyl chloride under standard con-
ditions to give 4 (Scheme 1). The diallyl 4 was subjected
to RCM reaction using Grubbs’ first generation catalyst.
It is interesting to note, that all RCM reactions of this
work were performed using the same concentration (see
experimental). When TLC analysis confirmed consump-
tion of the starting material, the reaction was stopped and
subsequent silica gel column chromatography afforded
Olefin metathesis has been established as a very interest-
ing, important and general reaction in synthetic organic
chemistry and has attracted considerable attention in the
last decade with respect to forming cyclic olefins. This re-
action has been used in intramolecular cyclizations, which
lead to the formation of N- and/or O-heterocyclic com-
pounds.1 The reaction proceeds through the formation of
a new carbon–carbon bond from two olefin groups. Two
C–C double bonds are cleaved and new C–C bonds are
formed to give new compounds.
In general, acyclic olefin precursors can successfully un-
dergo RCM to form five- to seven-membered ring system,
but the preparation of products with larger heterocyclic
rings is also achieved using olefin metathesis.2 Metathesis
has also seen a prolific use in the preparation of macrocy-
clic natural products from the corresponding diene sub-
strates.3
the nine-membered benzo-fused 1,5-diazanine
(Scheme 1).
5
Under these optimized reaction conditions, we examined
the application of RCM for other heterocyclic synthesis
such as quinoline, N-arylpyrrole and furan compounds.
Literature review revealed several RCM conditions for
the synthesis of dihydroquinolines from different precur-
sors using ruthenium catalyst.8 Neither of these articles
however provided the preparation of quinolines and qui-
nolones from simple acetanilides using the dichloro(ben-
zylidene)bis(tricyclohexylphosphine)ruthenium (I) as
catalyst. We tried to synthesize the dihydroquinoline 10,
which is a useful heterocycle for the synthesis of biologi-
cally active compounds.
The commercially available Grubbs’ first-generation cat-
alyst (Grubbs’ carbene) has high functional-group toler-
ance and it is relatively moisture- and air-stable. The
second-generation Grubbs’ ruthenium catalyst possesses
in general a very good application profile and shows en-
hanced RCM activity compared to its parent I, but it is
more expensive.4
Recently, several investigations have been made in the
field of the metathesis of various types of dienes.5 In this
paper, we describe an extension of RCM reaction to the
synthesis of N- and/or O-heterocycles of nine, six and five
atoms using a ruthenium catalyst and the reaction condi-
tions. The metathesis reactions were carried out using
dichloro(benzylidene)bis(tricyclohexylphosphine)ruthe-
nium as catalyst in benzene at 60 °C. Treatment of dienes
with Grubbs’ catalyst under mild RCM conditions did not
The crude diene 9 was prepared by dehydration of the cor-
responding hydroxyamide 8 using P2O5 under reflux con-
ditions. Treatment of the hydroxyamide
8 with
trifluoroacetic anhydride (TFA) afforded the tetrahydro-
quinolone 12 instead of the diene 9. The compound 12
was formed by intramolecular cyclization of the aceta-
mide group to the benzylic position. The alcohol 8 was
prepared by direct ortho-lithiation of the acetamide 7 with
SYNTHESIS 2006, No. 11, pp 1823–1828
x
x.
x
x
.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942360; Art ID: Z22305SS
© Georg Thieme Verlag Stuttgart · New York

1824
I. Sánchez, M. D. Pujol
PAPER
NO2
NCOOEt
NHCOOEt
NHCOOEt
NO2
iii
i
ii
NHBn
Bn
1
2
3
COOEt
N
COOEt
N
PCy3
Ru
Cl
Cl
Ph
iv
N
PCy3
N
COOEt
4
5
Grubbs' Catalyst (I)
COOEt
Scheme 1 Reagents and conditions: (i) ethyl chloroformate, Et3N, CH2Cl2 (92%); (ii) a) H2, Pd/C, MeOH (95%), b) ethyl chloroformate,
Et3N, CH2Cl2 (67%); (iii) NaH, allyl chloride, DMF (64%); (iv) with I (5 mol%), benzene, 60 °C (54%), with I (5 mol%), toluene, 60 °C (48%),
with I (5 mol%), toluene, reflux (51%), with I (5 mol%), CH2Cl2, reflux (36%).
t-BuLi followed by treatment with acetaldehyde. RCM of subjected to RCM conditions. Finally the dehydrogena-
the diene 9 afforded the 1,4-dihydroquinoline 10. In the tion of 15 with Pd/C in decalin leads to the N-arylpyrrole
course of this reaction the acetyl protecting group was 16 (Scheme 3). The analytical data of 16 are in agreement
cleaved and the double bound isomerized. Immediately, with results described in the literature.15
the dihydroquinoline was readily converted to the quino-
line 119 in quantitative yield by treatment with Pd/C in
NH2
decalin10 (Scheme 2). Also was observed, that 10 was
spontaneously oxidized to 11 on contact with oxygen, al-
though more slowly than when the reaction mixture was
treated with oxidative reagents.
N
N
N
i
ii
iii
13
F
F
14
16
F
F
15
In the classical reactions, the most direct formation of pyr-
roles requires an enolizable 1,4-dicarbonylic compound
(Paal–Knorr reaction), and usually require drastic reaction
conditions.11 More recently, Evans and coworkers12 and
Yang et al.13 have prepared pyrrole nucleus using rutheni-
um-catalyzed RCM, and Stevens et al.14 provided a more
general RCM method using a combination of second gen-
eration Grubbs’ catalyst and ruthenium(III) chloride.
Scheme 3 Reagents and conditions: (i) NaH, allyl chloride, DMF
(47%); (ii) with I (5 mol%), benzene, 60 °C (79%), with I (5 mol%),
toluene, 60 °C (74%), with I (5 mol%), toluene, reflux (54%), with I
(5 mol%), CH2Cl2, reflux (14%); (iii) Pd/C in decalin (89%).
Finally, the extension of this strategy towards the synthe-
sis of spirofuropiperidines as potentially valuable func-
tionalized 1,3-dienes from the N-benzyl-4-piperidone
In this context, we envisaged the possibility that N-aryl- (17) was attempted. The strategy of our synthesis of the
pyrroles could be synthesized through RCM reaction of diene 20 is presented in Scheme 4. The dihydrofuran ring
appropriate diallylanilines. The diallyl compound 14 was of 20 could be constructed at the last stage of the synthesis
found to be an excellent substrate for RCM reaction to the by RCM. The piperidone 17 was treated with lithium
formation of N-arylpyrrole. The N-(3-fluorophenyl)pyr- acetylide in THF at –78 °C to give after hydrolysis at
role (16) was prepared in three steps from commercially room temperature the tertiary alcohol 18. This alcohol
available 3-fluoroaniline (13) which was first converted was then reacted with allyl chloride to afford the allyloxy
into the tertiary amine 14 by standard methods and then derivate 19. The intramolecular enyne metathesis
NHCOMe
NCOMe
NCOMe
NCOMe
i
v
ii
+
OH
N
H
7
6
9
8
10
iii
iv
vi
N
O
N
11
Me
12
Scheme 2 Reagents and conditions: (i) NaH, allyl chloride, DMF (50%); (ii) t-BuLi, CH3CHO (50% for 8 and 15% for 9); (iii) P2O5, CH2Cl2
(86%); (iv) CF3CO2COCF3, toluene, r.t. (43%); (v) with I (5 mol%), benzene, 60 °C (52%), with I (5 mol%), toluene, 60 °C (45%), with I (5
mol%), toluene, reflux (41%), with I (5 mol%), CH2Cl2, reflux (32%); (vi) Pd/C in decalin (92%).
Synthesis 2006, No. 11, 1823–1828 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocyclics by RCM
1825
reaction16 gives the formation of a new C–C bond between
the internal C of the double bond and the internal C of the
triple bond, and the alkylidene part of the alkene of 19 mi-
grates onto the alkyne carbon to form a new diene moiety
20.
corresponding N- or O-allyl derivative. The allylated compounds
are listed below.
Ring-Closing Metathesis Reaction; General Procedure
Ru catalyst I (5 mol%) was added to a stirring solution of the requi-
site diene 4, 9, 14 or 19 in anhyd and degassed benzene (0.02 M) un-
der argon. The mixture was heated at 60 °C until complete
consumption of starting materials (TLC). The solution was concen-
trated under reduced pressure and purified by chromatography. Col-
umn chromatography of the residue on silica gel using appropriate
mixture of EtOAc–hexane as eluent afforded analytically pure the
corresponding heterocyclic system. Reaction time and temperature
were optimized in each case. Yields indicated are for purified com-
pounds. The products are listed below.
O
O
O
C
CH
HO
C
CH
ii
i
iii
N
N
N
N
Bn
Bn
Bn
Bn
17
18
19
20
Scheme 4 Reagents and conditions: (i) LiC2H,THF, –78 °C (56%);
(ii) NaH, allyl chloride, DMF (64%); (iii) with I (5 mol%), benzene,
60 °C (76%), with I (5 mol%), toluene, 60 °C (61%), with I (5 mol%),
toluene, reflux (55%), with I (5 mol%), CH2Cl2, reflux (37%).
N-Benzyl-2-nitrobenzylamine (1)
To a stirred solution of 2-nitrobenzyl chloride (2 g, 11.6 mmol) in
distilled DMF (5 mL) were added the corresponding benzylamine
(2.5 mL, 23.5 mmol) and K2CO3 (3.2 g, 23.5 mmol). The mixture
was stirred for 6 h at 90 °C under argon and brought to r.t. Then the
reaction mixture was hydrolyzed with H2O (5 mL) and extracted
We have obtained in a straightforward manner, two new
heterocyclic compounds from dialkenes or alkyne-alk- with Et2O (3 × 20 mL). The organic layer was washed with H2O in
order to remove the DMF. The combined organic layers were dried
enes using dichloro(benzylidene)bis(tricyclohexyl phos-
(Na2SO4), filtered and the solvent was removed under reduced pres-
phine)ruthenium as catalyst. Several substrates were
sure. The resulting residue was purified by silica gel column chro-
examined, and new heterocyclic systems containing five,
matography (hexane–EtOAc) to give the corresponding amine 1 as
six and nine atoms were prepared under the same reaction
a yellow oil; yield: 2.17 g (77%).
conditions. In addition to the novelty of the compounds
prepared, this is the first report of the synthesis of spiro fu-
ropiperidines and 1,4-diazanine using metathesis method-
ology. This method is currently being applied to the
synthesis of other heterocyclic systems, which might be
intermediates for the preparation of biologically active
compounds.
IR (KBr): 3205, 1489, 1340, 1240 cm–1.
1H NMR (CDCl3, 200 MHz): d = 3.81 (s, 2 H, CH2Ar), 4.05 (s, 2 H,
CH2Ar), 7.18–7.34 (m, 5 H, Ar), 7.43 (m, 3 H, Ar), 7.92 (d, J = 8
Hz, 1 H, H-6).
13C NMR (CDCl3, 50.3 MHz): d = 46.9 (CH2Ar), 53.6 (CH2Ar),
125.3 and 127.8 (C-3 and C-4), 127.0 (C-4¢), 128.4 (C-2¢, C-6¢),
128.7 (C-3¢ and C-5¢), 129.5 (C-6), 133.8 (C-5), 134.7 and 137.1 (C-
1 and C-1¢), 148.5 (C-2).
Melting points were obtained on an MFB-595010M Gallenkamp
apparatus in open capillary tubes and are uncorrected. IR spectra
were obtained using a FTIR PerkinElmer 1600 IR Spectrophoto-
Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.15; H, 6.03; N, 11.78.
meter. Only noteworthy IR absorptions are listed (cm–1). 1H and 13
C
N-Benzyl-N-ethoxycarbonyl-2-nitrobenzylamine (2)
A mixture of the nitrobenzylamine (1; 1.0 g, 4.13 mmol), ethyl chlo-
roformate (0.6 mL, 6.2 mmol) and Et3N (0.9 mL, 6.2 mmol) in an-
hyd CH2Cl2 was stirred at r.t. for 24 h. Then the residue was
extracted with CH2Cl2, dried (Na2SO4), filtered and the solvent re-
moved. The crude of reaction was purified by silica gel column
chromatography (hexane–EtOAc) to afford 1.2 g (92%) of 2 as a
yellow oil.
NMR spectra were recorded on a Varian Gemini-200 (200 and 50.3
MHz respectively) or Varian Gemini-300 (300 and 75.5 MHz) in-
strument using CDCl3 as solvent with tetramethylsilane as internal
1
standard or acetone-d6. Other H NMR spectra and heterocorrela-
tion 1H-13C (HMQC and HMBC) experiments were recorded on a
Varian VXR-500 (500 MHz). Mass spectra were recorded on a
Hewlett-Packard 5988-A. Column chromatography was performed
with silica gel (E. Merck, 70–230 mesh). Reactions were monitored
by TLC using 0.25 mm silica gel F-254 (E. Merck). Microanalysis
was determined on a Carlo Erba-1106 analyzer. All reagents were
of commercial quality or were purified before use. Organic solvents
were of analytical grade or were purified by standard procedures.
Commercial products were obtained from Sigma-Aldrich.
IR (KBr): 1778, 1502, 1210 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.25 (t, J = 7.2 Hz, 3 H, CH3), 4.20
(q, J = 7.2 Hz, 2 H, CH2O), 4.51 (s, 2 H, CH2Ph), 4.80 (s, 2 H,
CH2Ph), 7.25–7.30 (m, 7 H, Ar), 7.60 (t, J = 8 Hz, 1 H, H-4), 8.05
(d, J = 8 Hz, 1 H, H-6).
13C NMR (CDCl3, 50.3 MHz): d = 14.7 (CH3), 47.2 (CH2Ar), 50.8
(CH2Ar), 61.9 (CH2O), 125.0 and 127.5 (C-3 and C-4), 127.8 (C-
4¢), 128.4 (C-2¢, C-6¢), 128.6 (C-3¢ and C-5¢), 130.1 (C-6), 133.5 (C-
5), 132.0 (C-1), 136.8 (C-1¢), 148.2 (C-2), 156.8 (C=O).
N- or O-Allylation; General Procedure
To a stirred suspension of NaH (60%, 2 mmol) in distilled DMF (5
mL) were added the corresponding amine 3, 6, 13 or 18 or alcohol
(1 mmol) and allyl chloride (5 mmol). The mixture was stirred for
6 h at 90 °C under argon. The mixture was warmed to r.t. and then
allyl chloride was added three times (each 1 mmol) and heating was
continued. Then the reaction mixture was hydrolyzed with H2O (5
mL) and extracted with Et2O (3 × 20 mL). The organic layer was
washed with H2O in order to remove the DMF. The combined or-
ganic layers were dried (Na2SO4), filtered and the solvent was re-
moved under reduced pressure. The resulting residue was purified
by silica gel column chromatography (hexane–EtOAc) to give the
2-(N-Ethoxycarbonylaminomethyl)-N-ethoxycarbonylaniline
(3)
A solution of the nitro compound 2 (828 mg, 2.6 mmol) in MeOH
(20 mL) was catalytically hydrogenated over 5% Pd/C (42 mg) at
atmospheric pressure until the starting material was consumed
(TLC). After removal of the catalyst by filtration, the filtrate was
evaporated in vacuum to dryness. Pure 2-(N-ethoxycarbonylami-
nomethyl)aniline (537 mg, 95%) was obtained as a solid by chroma-
Synthesis 2006, No. 11, 1823–1828 © Thieme Stuttgart · New York

1826
I. Sánchez, M. D. Pujol
PAPER
tography over a silica gel column (hexane–EtOAc); mp 78–80 °C
(hexane–EtOAc).
N-(Prop-2-enyl)acetanilide (7)
Compound 7 was obtained from the acetanilide 6 (2 g, 15 mmol) by
allylation following the general procedure described before; yield:
1.2 g (50%).
1H NMR (CDCl3, 200 MHz): d = 1.81 (s, 3 H, CH3), 4.24 (dd,
J = 1.2, 6.2 Hz, 2 H, CH2N), 5.00–5.11 (m, 2 H, CH2=), 5.75–5.85
(m, 1 H, CH=), 7.10 (d, J = 7.6 Hz, 2 H, H-2, H-6), 7.28–7.36 (m, 3
H, H-3, H-4, H-5).
2-(N-Ethoxycarbonylaminomethyl)aniline
IR (KBr): 3205, 1732, 1548, 1190 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.27 (t, J = 7 Hz, 3 H, CH3), 4.25
(q, J = 7 Hz, 2 H, CH2), 4.37 (s, 2 H, CH2Ph), 6.62–6.70 (m, 2 H, H-
4, H-6), 6.92 (m, 2 H, H-3, H-5).
A solution of the above intermediate aniline (853 mg, 4.4 mmol),
ethyl chloroformate (0.62 mL, 6.5 mmol) and Et3N (1.1 mL, 7.8
mmol) in anhyd CH2Cl2 (10 mL) was stirred at r.t. for 24 h. The
mixture was extracted with CH2Cl2 (3 × 20 mL), dried (Na2SO4),
filtered and evaporated to dryness in vacuum. The residue was pu-
rified by silica gel column chromatography (hexane–EtOAc). The
carbamate 3 was obtained as a yellow oil; yield: 778 mg (67%).
13C NMR (CDCl3, 50.3 MHz): d = 22.6 (CH3), 52.0 (CH2C), 117.7
(CH2=), 127.7 (CH=), 127.9 (C-2, C-4), 129.5 (C-3, C-5), 133.0 (C-
4), 142.8 (C-1), 169.9 (C=O).
Anal. Calcd for C11H13NO2: C, 75.40; H, 7.48; N, 7.99. Found: C,
75.23; H, 7.18; N, 7.78.
N-Acetyl-2-(2-hydroxyethyl)-N-(prop-2-enyl)aniline (8) and
N-(Prop-2¢-enyl)-2-vinylacetanilide (9)
IR (KBr): 3308, 1743, 1645, 1570, 1167 cm–1.
A stirred solution of the starting acetanilide 7 (500 mg, 2.85 mmol)
and TMEDA (0.9 mL, 5.7 mmol) in anhyd THF (5 mL) was cooled
at –78 °C and a solution of t-BuLi was added (3.35 mL, 1.7 M, 5.7
mmol). The mixture was stirred under argon for 3 h, then an excess
of acetaldehyde was added at –78 °C and allowed to warm slowly
to r.t. over 12 h. A solution of aq sat. NH4Cl was added (5 mL) and
the mixture extracted with Et2O (3 × 20 mL). The combined organic
extracts were dried (Na2SO4) and concentrated. The residue was pu-
rified by silica gel column chromatography (hexane–EtOAc) to
give the alcohol 8 as the major product; yellow solid; yield: 340 mg
(50%).
1H NMR (CDCl3, 200 MHz): d = 1.26–1.34 (m, 6 H, CH3), 4.14–
4.38 (m, 4 H, CH2), 4.38 (d, J = 5.6 Hz, 2 H, CH2Ph), 6.20–6.50 (m,
1 H, H-4), 7.20–7.54 (m, 3 H, Ar).
13C NMR (CDCl3, 50.3 MHz): d = 14.6 (CH3), 14.7 (CH3), 48.5
(CH2Ar), 60.9 (CH2O), 62.5 (CH2O), 127.4 (C-6), 127.5 (C-4),
128.6 (C-5), 129.1 (C-3), 124.9 (C-2), 136.7 (C-1), 155.2 (C=O),
155.7 (C=O).
Anal. Calcd for C13H18N2O4: C, 58.63; H, 6.81; N, 10.52. Found: C,
58.30; H, 6.45; N, 10.52.
1H NMR (CDCl3, 200 MHz): d = 1.33 (d, J = 6.2 Hz, 3 H, CH3),
2.52 (s, 3 H, CH3CON), 4.21–4.29 (t, J = 8 Hz, 1 H, CHO), 7.18 (t,
J = 8 Hz, 1 H, H-4), 7.30 (t, J = 8 Hz, 1 H, H-5), 7.24 (d, J = 8 Hz,
1 H, H-C), 7.48 (d, J = 8 Hz, 1 H, H-6), 7.80 (br s, 1 H, NH).
13C NMR (CDCl3, 50.3 MHz): d = 23.0 (CH3CO), 64.9 (CH2O),
120.1 (C-6), 124.4 (C-4), 128.9 (C-3, C-5), 132.1 (C-2), 137.5 (C-
1), 170.7 (C=O).
2-(N¢-Allyl-N¢-ethoxycarbonylaminomethyl)-N-allyl-N-ethoxy-
carbonylaniline (4)
Starting from 3 (708 mg, 2.6 mmol) and following the general pro-
cedure of allylation, compound 4 was obtained as a colorless oil;
yield: 587 mg (64%).
IR (KBr): 1724, 1534, 1203 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.25–1.28 (m, 6 H, CH3), 3.81–
3.97 (m, 2 H, CH2N), 3.99–4.20 (m, 4 H, CH2N), 4.22–4.40 (m, 4
H, CH2O), 5.08 (d, J = 16 Hz, 4 H, CH2=), 5.76–5.94 (m, 2 H,
CH=), 7.02–7.29 (m, 4 H, H-3 to H-6).
13C NMR (CDCl3, 50.3 MHz): d = 14.6 (CH3), 14.7 (CH3), 49.5
(CH2Ar), 53.1 (2 × CH2CH=), 61.6 (CH2O), 61.7 (CH2O), 118.3
(2 × CH2=), 127.3, 127.7, 128.1, 128.5 (CH, Ar), 132.9 (2 × CH=),
134.0 (C-2), 138.5 (C-1), 156.8 (C=O).
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
71.45; H, 7.65; N, 6.23.
The dehydrated compound 9 was obtained as a by-product; yellow
oil; yield: 87 mg (15%).
9
1H NMR (CDCl3, 200 MHz): d = 1.73, 1.78 (s, 3 H, rotamers A and
B, CH3CON), 4.36 (d, J = 5.8 Hz, 2 H, CH2N), 5.10–5.21 (m, 2 H,
allyl CH2=), 5.72-5.88 (m, 3 H, allyl CH=, vinyl CH2=), 6.95–7.04
(m, 1 H, vinyl CH), 7.22–7.34 (m, 4 H, Ar).
Anal. Calcd for C27H30N2O4: C, 72.62; H, 6.77; N, 6.27. Found: C,
72.40; H, 6.54; N, 6.02.
13C NMR (CDCl3, 50.3 MHz): d = 27.8 (CH3CO), 52.3 (CH2N),
117.5 (CH2=), 117.6 (CH2=), 122.7 (C-6), 128.1 (C-4), 128.8 and
129.2 (C-3, C-5), 132.0 (C-2), 133.1 (CH=), 141.5 (CH2CH=),
142.0 (C-1), 166.0 (C=O).
1,6-Diethoxycarbonyl-2,5,6,7-tetrahydro-1H-1,6-benzodiaza-
nine (5)
The diamino cyclized compound 5 was obtained as a colorless oil
from the corresponding diallyl derivative 4 (100 mg, 0.3 mmol) fol-
lowing the general procedure described above for the RCM; yield:
60 mg (54%).
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.38; H, 7.30; N, 6.75.
IR (KBr): 1213, 1415, 1678 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.26 (br s, 6 H, CH3), 3.56 (s, 2 H,
CH2N), 3.95–4.12 (m, 2 H, CH2N), 4.12–4.26 (m, 4 H, CH2O),
4.29–4.37 (m, 2 H, CH2N), 5.48–5.56 and 6.84–7.02 (m, 2 H, H-3,
H-4), 7.12–7.30 (m, 4 H, Ar).
13C NMR (CDCl3, 50.3 MHz): d = 14.6 and 14.7 (CH3), 45.5, 49.4
and 52.0 (CH2N), 61.7 (2 × CH2O), 127.3, 127.8, 128.5, 128.9 (CH,
Ar), 128.7 (CH=CH), 135.0 and 138.0 (C-7a, C-11a), 157.0 (C=O),
158.7 (C=O).
1,4-Dihydroquinoline (10)
The dihydroquinoline 10 was obtained following the general proce-
dure of RCM from the starting diene 9 (50 mg, 0.25 mmol); yield:
52%; yellow oil.
IR (KBr): 3021, 1523, 1498 cm–1.
1H NMR (CDCl3, 200 MHz): d = 4.46 (t, J = 1.8 Hz, 2 H, CH2),
6.25–6.32 (m, 1 H, H-3), 7.12–7.20 (m, 2 H, NH, H-2), 7.38 (t, J = 8
Hz, 2 H, H-6, H-7), 7.70 (d, J = 7.6 Hz, 2 H, H-5, H-8).
13C NMR (CDCl3, 50.3 MHz): d = 53.2 (CH2), 118.5 and 118.8 (C-
6, C-7), 124.2 (C-3), 128.5 (C-4a), 129.0 and 129.2 (C-5, C-8),
140.0 (C-8a), 142.1 (C-2).
Anal. Calcd for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20. Found: C,
62.89; H, 6.45; N, 8.97.
Synthesis 2006, No. 11, 1823–1828 © Thieme Stuttgart · New York

PAPER
Synthesis of Heterocyclics by RCM
1827
Anal. Calcd for C9H9N: C, 82.41; H, 6.92; N, 10.68. Found: C,
82.59; H, 6.75; N, 10.89.
13C NMR (CDCl3, 50.3 MHz): d = 62.6 (2 × CH2N), 110.8 (C-3 and
C-4), 111.2 (C-4¢, J = 24 Hz), 118.9 (C-6¢, J = 2.5 Hz), 123.9 (C-2¢,
J = 24.3 Hz), 130.1 (C-5¢, J = 10.5 Hz), 139.6 (C-1¢, J = 12 Hz),
148.2 (C-3¢, J = 256 Hz).
Quinoline (11)
A solution of 10 (200 mg, 1.5 mmol) in decalin (5 mL) was added
5% Pd/C (10 mg). The resulting mixture was heated at 220 °C and
stirred for 24 h. Finally the suspension was filtered and the solvent
was removed by distillation. The purification by silica gel column
chromatography (hexane–EtOAc) gave the quinoline (11) in 92%
yield. The analytical data are in agreement with the results de-
scribed for the commercial compound.9
16
The analytical data of 16 are in agreement with the results described
in the literature.15
N-Benzyl-4-ethynyl-4-hydroxypiperidine (18)
To a stirred solution of N-benzyl-4-piperidone (17; 500 mg, 2.6
mmol) in anhyd THF (10 mL) under argon and cooled at –10 °C was
slowly added lithium acetylide (359 mg, 3.9 mmol). The mixture
was stirred for 20 min at –10 °C and allowed to warm to r.t. Then
aq sat. NH4Cl was added (5 mL) and the residue extracted with Et2O
(3 × 20 mL). The combined organic extracts were washed with
brine, dried (Na2SO4), filtered and the solvent removed. The silica
gel column chromatography of the crude product (hexane–EtOAc)
gave compound 18 as a yellow oil; yield: 305 mg (56%).
N-Allyl-4-methyl-3,4-dihydro-1H-2-quinolone (12)
A solution of the alcohol 8 (160 mg, 0.73 mmol) and trifluoracetic
anhydride (0.5 mL) in toluene (5 mL) was stirred at r.t. for 24 h. The
crude mixture was extracted with Et2O (3 × 10 mL), dried
(Na2SO4), filtered and concentrated. The purification by silica gel
column chromatography (hexane–EtOAc) gave the unexpected
2-quinolone 12; yellow oil; yield: 63.1 mg (43%).
IR (neat): 1728, 1495, 1345 cm–1.
IR (KBr): 3323, 2210, 1589, 1415, 1234 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.85–1.98 (m, 4 H, CH2C), 2.36–
2.45 (m, 2 H, CH2Nax), 2.50 (s, 1 H, C≡CH), 2.64–2.72 (m, 2 H,
CH2Neq), 3.52 (s, 2 H, CH2Ar), 7.25–7.32 (m, 5 H, Ar).
1H NMR (CDCl3, 200 MHz): d = 1.32 (d, J = 6.2 Hz, 3 H, CH3),
2.25 (dd, J = 1.8, 12 Hz, 1 H, CHC), 2.58 (dd, J = 6, 12 Hz, 1 H,
CHC), 4.25–4.34 (m, 2 H, CH2=), 5.10 (d, J = 8 Hz, 2 H, CH2N),
5.48 (q, J = 6.2 Hz, 1 H, CH), 7.13–7.18 (m, 2 H, Ar), 7.40–7.46 (m,
2 H, Ar).
13C NMR (CDCl3, 50.3 MHz): d = 22.1 (CH3), 41.7 (CH2), 52.2
(CH2), 64.9 (CH), 118.3 (CH2=), 128.0 (C-6), 128.1 (C-7), 128.3
(C-4a), 129.7 and 129.8 (C-5, C-8), 132.3 (CH=), 142.0 (C-8a),
172.5 (C=O).
13C NMR (CDCl3, 50.3 MHz): d = 38.9 (CH2C), 49.7 (CH2N), 62.6
(CH2), 72.5 (C–OH), 82.3 (C≡CH), 86.5 (C≡CH), 126.9 (C-4¢),
128.2 (C-2¢, C-6¢), 128.9 (C-3¢, C-5¢), 132.4 (C-1¢).
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.50. Found: C,
77.78; H, 7.59; N, 6.72.
N-Benzyl-4-ethynyl-4-(prop-2-enyloxy)piperidine (19)
Compound 19 was obtained from the alcohol 18 (100 mg, 0.5
mmol) following the general procedure described above; yield: 75
mg (64%).
1H NMR (CDCl3, 200 MHz): d = 1.86–1.98 (m, 4 H, CH2C), 2.35–
2.46 (m, 2 H, CH2Nax), 2.50 (s, 1 H, C≡CH), 2.60–2.70 (m, 2 H,
CH2Neq), 3.56 (s, 2 H, CH2Ar), 4.11 (t, J = 5.6 Hz, 2 H, CH2O),
5.15 (dd, J = 2, 16 Hz, 2 H, CH2=), 5.84–6.02 (m, 1 H, CH=), 7.24–
7.33 (m, 5 H, Ar).
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C,
77.89; H, 7.31; N, 6.65.
N,N-Diallyl-N-(3-fluoro)aniline (14)
From 3-fluoroaniline (1 g, 9 mmol), NaH (60% in mineral oil, 720
mg, 18 mmol) and allyl chloride (3.6 mL, 45 mmol), the diene 14
was obtained as an oil (528 mg, 47%). The corresponding mono-
allyl compound was also obtained under these conditions; yield:
360 mg (27%).
IR (KBr): 1540, 1210 cm–1.
13C NMR (CDCl3, 50.3 MHz): d = 36.3 (CH2C), 49.7 (CH2N), 62.6
(CH2), 64.6 (CH2O), 75.5 (C–O), 76.6 (C≡CH), 96.3 (C≡CH), 116.4
(=CH2), 127.0 (C-4¢), 128.1 (C-2¢, C-4¢), 129.0 (C-3¢, C-5¢), 131.6
(C-1¢), 135.0 (CH=).
1H NMR (CDCl3, 200 MHz): d = 3.90–3.93 (m, 4 H, CH2N), 5.14–
5.20 (m, 4 H, CH2=), 5.80–5.90 (m, 2 H, CH=), 6.62–6.72 (m, 3 H,
H-2, H-4, H-6), 7.15–7.25 (m, 1 H, H-5).
Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N, 5.48. Found: C,
79.62; H, 8.09; N, 5.26.
13C NMR (CDCl3, 50.3 MHz): d = 52.8 (2 × CH2N), 99.2 (J = 26
Hz, C-2), 102.5 (J = 22 Hz, C-4), 107.7 (J = 2.3 Hz, C-6), 116.1
(2 × CH2=CH), 129.9 (J = 10.5 Hz, C-5), 133.3 (2 × CH=), 150.0
(C-1, J = 10 Hz), 162.1 (C-3, J = 251 Hz).
Spiro(N-benzylpiperidine)-4,2¢-(4¢-vinyl-2¢,5¢-dihydrofuran)
(20)
The spiro compound 20 was synthesized from 19 (16 mg, 0.06
mmol) following the general procedure of RCM; oil; yield: 13 mg
(76%).
IR (KBr): 1523, 1251 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.96–2.04 (m, 4 H, CH2C), 2.30–
2.45 (m, 2 H, CH2Nax), 2.75–2.85 (m, 2 H, CH2Neq), 3.55 (s, 2 H,
CH2Ar), 4.59 (d, J = 1.8 Hz, 2 H, CH2O), 5.15 (d, J = 12 Hz, 1 H,
CH2=), 5.55 (d, J = 20 Hz, 1 H, CH2=), 5.85 (t, J = 2.4 Hz, 1 H, H-
3), 6.20 (dd, J = 20, 12 Hz, 1 H, C=CH), 7.24–7.32 (m, 5 H, Ar).
Anal. Calcd for C12H14FN: C, 75.36; H, 7.38; N, 9.93. Found: C,
74.99; H, 7.28; N, 9.62.
N-(3-Fluorophenyl)-2,5-dihydropyrrole (15) and N-(3-Fluoro-
phenyl)pyrrole (16)
The dihydropyrrole 15 was obtained starting from the diene 14 (100
mg, 0.5 mmol) and following the general procedure of RCM. The
high instability of 15 gave spontaneously the pyrrole derivative 16.
15
Colorless oil; yield: 67 mg (79%).
IR (KBr): 1536, 1499, 1305, 720 cm–1.
1H NMR (CDCl3, 200 MHz): d = 4.08 (s, 4 H, CH2), 5.94 (s, 2 H,
CH=), 6.19–6.28 (m, 3 H, H-2¢, H-4¢, H-6¢), 7.10–7.26 (m, 1 H, H-
5¢).
13C NMR (CDCl3, 50.3 MHz): d = 40.2 (CH2C), 48.2 and 51.2
(CH2N), 64.1 (CH2O), 94.1 (C-4), 110.8 (CH=CH2), 126.8 (C-4¢¢),
128.2 (C-2¢¢, C-6¢¢), 129.0 (C-3¢¢, C-5¢¢), 138.1 (C-1¢¢), 133.2
(CH2=C), 136.2 (CH=).
Anal. Calc. for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C,
79.89; H, 7.99; N, 5.77.
Synthesis 2006, No. 11, 1823–1828 © Thieme Stuttgart · New York

1828
I. Sánchez, M. D. Pujol
PAPER
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Acknowledgment
Financial support for this work was provided by the Ministerio de
Ciencia y Tecnología (MCYT, BQU 2002-00148), and the Comis-
sionat per a Universitats i Recerca de la Generalitat de Catalunya,
Spain (2005-SGR-00180).
(6) Bourlot, A. S.; Sánchez, I.; Dureng, G.; Guillaumet, G.;
Massingham, R.; Monteil, A.; Winslow, E.; Pujol, M. D.;
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Synthesis 2006, No. 11, 1823–1828 © Thieme Stuttgart · New York