Sequential N-acylamide methylenation-enamide ring-closing metathesis: A synthetic entry to 1,4-dihydroquinolines

Article abstract of DOI:10.1016/j.tetlet.2005.04.028

A new synthetic entry to the 1,4-dihydroquinoline nucleus is reported. The procedure involves the dimethyltitanocene methylenation of N-(alkoxycarbonyl) amides derived from 2-allylanilines, followed by ring-closing metathesis of the resulting enamides.

Full text of DOI:10.1016/j.tetlet.2005.04.028

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4035–4038
Sequential N-acylamide methylenation–enamide ring-closing
metathesis: a synthetic entry to 1,4-dihydroquinolines
*
M.-Llu¨ısa Bennasar, Tomas Roca, Manuel Monerris and Davinia Garcıa-Dıaz
`
´
´
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received 3 March 2005; revised 6 April 2005; accepted 6 April 2005
Available online 20 April 2005
Abstract—A new synthetic entry to the 1,4-dihydroquinoline nucleus is reported. The procedure involves the dimethyltitanocene
methylenation of N-(alkoxycarbonyl)amides derived from 2-allylanilines, followed by ring-closing metathesis of the resulting
enamides.
Ó 2005 Elsevier Ltd. All rights reserved.
Ruthenium-catalysed ring-closing metathesis (RCM)
reactions1 are well-established processes for the synthe-
1. Olefination
2. RCM
O
sis of nitrogen heterocycles, as illustrated by numerous
reports dealing with the efficient construction of com-
plex targets from suitable azadiene substrates.2 Cyclis-
ations involving x-alkenyl enamides,3 that is, azadienes
in which the nitrogen atom is directly connected to one
of the double bonds, are particularly interesting as the
resulting cyclic enamides4 constitute versatile moieties
amenable to further functionalisation.5 In this context,
we envisaged the possibility that a variety of benzo fused
bicyclic nitrogen compounds could be synthesised
through RCM reactions of appropriate enamides. For
the preparation of these substrates,6 we planned to take
advantage of olefination protocols, which, in combin-
ation with RCM, would make our heterocyclic targets
conveniently available from olefinic amides. In this letter
we report our preliminary results concerning the use of
this amide olefination–enamide RCM reaction sequence
for the construction of 1,4-dihydroquinoline system,
starting from N-protected amides derived from 2-allyl-
anilines (Scheme 1). This scheme would complement
existing RCM-based syntheses of 1,2-dihydroquinolines
from different precursors.7
1
R1
N
R
N
R1 = H, Me
R2 = acyl or
sulfonyl
R2
R2
Scheme 1.
and co-workers,10 and, to a lesser extent, Petasis reagent
(dimethyltitanocene, Cp2TiMe2)11 have proven to be
very effective for the methylenation of esters.12 Subse-
quent RCM of the resulting enol ethers is the key step
of several brilliant approaches to cyclic enol ethers.8,13
On the other hand, the methylenation of amides has
clearly received less attention,8 dimethyltitanocene
appearing to be the reagent of choice,14,15 in particular
with N-protected lactams.16
Considering the above precedents, we set out to explore
the behaviour of dimethyltitanocene with easily accessi-
ble model substrates, such as anilides 1 and 2, which bear
different electron-withdrawing substituents (sulfonyl or
alkoxycarbonyl) at the nitrogen. Dimethyltitanocene
was prepared by treatment of titanocene dichloride with
methyl-lithium, following the reported procedure,11 and
was immediately treated with the amide substrate in
toluene at reflux under conditions A or B (see Table 1).17
Their ability to olefinate carboxylic acid derivatives
makes titanium-based complexes distinctive reagents in
organic synthesis.8 Among them, the Tebbe,9 Takai
Our first assays using N-tosylacetanilide (1a) were dis-
couraging since deacetylation rapidly took place in both
conditions tried (A or B) to give aniline 5a as the only
product (entry 1). This undesired process could only
Keywords: Dimethyltitanocene; Olefination; Enamides; Ring-closing
metathesis; 1,4-Dihydroquinolines.
*
Corresponding author. Tel.: +34 934024540; fax: +34 934024539;
e-mail: bennasar@ub.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.028

4036
M.-L. Bennasar et al. / Tetrahedron Letters 46 (2005) 4035–4038
Table 1. Reaction of model anilides 1 and 2 with Cp2TiMe2
favoured in these series due to the presence of strong
electron-withdrawing N-sulfonyl groups.
CH2
R1
O
Cp2TiMe2
In full accordance with this proposal, no deacetylation
was observed when the reaction was effected from acet-
anilides 1c and d, which bear weaker electron-withdraw-
ing N-alkoxycarbonyl groups. The best results were
obtained from N-Boc derivative 1c, providing enamide
3c in high isolated yield (85%, entry 4). Similarly, N-
(methoxycarbonyl)acetanilide 1d gave enamide 3d in
good yield (75%, entry 5). However, in this case minor
amounts of acetanilide (6), coming from the competitive
interaction of the reagent with the methoxycarbonyl
group, were detected in the reaction mixtures. Probably
for steric reasons, the chemoselectivity was again com-
plete in the reaction of formanilide 2d, resulting in the
unstable enamide 4d as the only product (40% isolated
yield, entry 6).
N
N
R1
conditions
A or B
R2
R2
3 R1 = Me
4 R1 = H
1 R1 = Me
2 R1 = H
O
a R2 = Ts
b R2 = Ms
+
+
NH
c R2 = Boc
d R2 = CO2Me
N
H
Me
R2
5
6
Entry Substrate Conditionsa Products Isolated yields (%)
b
1
2
3
1a
1b
1b
A or B
5a
5b
b
A
B
3b + 5b
(2.5:1)c
3
10d
4
5
1c
1d
A or B
B
c
85
75
At this point, we wondered whether the dimethyltitano-
cene methylenation of N-sulfonylamides derived from
aliphatic amines would take place, assuming that the
elimination process depicted in Scheme 2 would be less
favoured, given the presence of a poorer leaving group.
Effectively, when submitted to the standard methylen-
ation conditions, N-mesylacetamide 7a cleanly afforded
enamide 8a (65% yield) without significant deacetylation
(Scheme 3). On the other hand, the related enamide 8b
was obtained in 75% yield from N-(methoxycar-
bonyl)acetamide 7b.
3d + 6
(10:1)c
4d
6
2d
B
40d
a Conditions A: Cp2TiMe2 (2mol), toluene, reflux, 12h; B: Cp2TiMe2
(1.5 mol), 100:1 toluene–pyridine, reflux, 4 h.
b Total conversion determined by 1H NMR.
c Ratio determined by 1H NMR.
d Unstable enamide, which partially decomposes under chromato-
graphic purification.
be minimised from N-mesyl derivative 1b under milder
(B) conditions to give a 2.5:1 mixture of the expected
enamide 3b and aniline 5b (entry 3). Unfortunately, iso-
lation of 3b proved problematic as it was very sensitive
to chromatography.
Having established the limitations of the methylenation
of N-protected anilides, we turned our attention to the
preparation of RCM substrates for the construction of
the 1,4-dihydroquinoline system, that is, enamides
which incorporate the ortho-allyl substituent needed
for the ring-closure step. The required amide precursors
9 and 10 were easily prepared by conventional acylation
protocols starting from 2-allylaniline,19 as shown in
Scheme 4.
Given that the deacetylated products 5a and b were
already present in the crude reaction mixtures, their
formation is hard to attribute to a fortuitous hydrolysis
of enamides 3a and b. A plausible explanation is that the
oxatitanacyclobutane intermediate A, coming from the
initial interaction of the titanium carbene with the car-
bonyl group of 1a and b, undergoes at least partial elim-
ination of the sulfonylamino moiety as depicted in
Scheme 2, rather than the expected transfer of the meth-
ylene group.18 This process would be particularly
The dimethyltitanocene methylenation was first per-
formed with acetanilides 9a and b under the previous
conditions17 (B, see Table 1). Satisfactorily, both en-
amides 11a and b20 were isolated in consistent, repro-
ducible 55% and 51% yield, respectively (Scheme 5). In
the latter case, significant amounts (20%) of acetanilide
(17) were also obtained, reflecting again (see Table 1,
entry 5) an incomplete discrimination between the amide
and carbamate carbonyl groups. As anticipated,3 en-
amides 11a and b underwent RCM upon treatment with
the second generation Grubbs catalyst (18) at 80 °C in
toluene.21 The cyclisation proved to be unaffected by
the steric hindrance of the enamide moiety, as both sub-
strates gave the expected 1,4-dihydroquinolines 13a and
Cp2
Ti
O
O
Cp2Ti=CH2
N
Me
N
Me
R2
R2
1
A
R2 = sulfonyl
CH2
– Cp2Ti=O
X = Ph(R2)N
CH2
R
N
R
N
Cp2TiMe2
(1.5 mol)
XCp2TiO
Me
Me
Me
CH2
N
Me
O
R2
O
7
8
3
a R = Ms 65%
5
+
b R = CO2Me 75%
Me
Me
Scheme 2.
Scheme 3.

M.-L. Bennasar et al. / Tetrahedron Letters 46 (2005) 4035–4038
4037
a, b
c, d
CH2
Me
O
a R = Boc
b R = CO2Me
NH2
e, b
N
R
NH
R
N
Me
Boc
9a (80%)
19
20
Figure 1.
anocene in combination with a ruthenium-catalysed
RCM step of the resulting enamides gives access to the
1,4-dihydroquinoline system.23 Further extension of this
reaction sequence to other heterocyclic systems is in
progress.
O
O
N
Me
N
H
CO2Me
Boc
10a (75%)
9b (80%)
Scheme 4. Reagents and conditions: (a) Ac2O, AcOH, reflux, 15 min;
(b) (Boc)2O, DMAP, Et3N, CH2Cl2, rt, 12h; (c) ClCO 2Me, pyridine,
THF, rt, 12h; (d) NaH, MeCOCl, CH 2Cl2, reflux, 20 h; (e) Ac2O–
HCO2H, 55 °C, 2h, then addition of the amine, THF, rt, 3 h.
Acknowledgements
Financial support from the ÔMinisterio de Ciencia y
´
TecnologıaÕ (MCYT-FEDER, Spain) through project
BQU2003-04967-C02-02 is gratefully acknowledged.
We also thank the DURSI (Generalitat de Catalunya)
for Grant 2001SGR00084 and for fellowships to M.M.
O
CH2
R1
a
b
R1
N
R1
N
N
´
and D.G.-D. Finally, we thank Professor Joaquın Plu-
met and Professor Aurelio G. Csaky (Department of
¨
R2
R2
R2
´
9 R1 = Me
10 R1 = H
13 R1 = Me
14 R1 = H
Organic Chemistry, Universidad Complutense de Ma-
drid) for fruitful discussions and their encouragement
throughout this investigation.
11 R1 = Me
12 R1 = H
a R2 = Boc
b R2 = CO2Me
MesN
Cl
Cl
18
NMes
References and notes
O
c
N
R1
Ru
PCy3
1. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003; Vol. 2.
N
Me
Ph
H
15 R1 = Me
17
16 R1 = H
2. For recent reviews on the application of the RCM to the
synthesis of nitrogen heterocycles, see: (a) Walters, M. A.
In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Joule, J. A., Eds.; Pergamon: Amsterdam, 2003, Vol. 15,
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2004, 104, 2127–2198; (c) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199–2238.
Scheme 5. Reagents and conditions: (a) Cp2TiMe2 (1.5 mol), 100:1
toluene–pyridine, reflux 4 h, 55% (11a), 51% (11b); (b) 6 mol% 18,
toluene, 0.1 M, 80 °C, 4 h, 75% (13a), 75% (13b), 45% (14a, from 10a);
(c) 5% Pd–C, O2, THF, reflux, 6 h, 80% (15), 85% (16).
3. For RCM reactions involving enamides, see: (a) Kinder-
man, S. S.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, P. J. T. Org. Lett. 2001, 3, 2045–
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Nishida, A. Angew. Chem., Int. Ed. 2002, 41, 4732–4734;
(c) Van Otterlo, W. A. L.; Pathak, R.; de Koning, C. B.
b22 in 75% yield. Similarly, when the methylenation-
RCM sequence was effected from formanilide 10a
the unstable 1,4-dihydroquinoline 14a was obtained
through enamide 12a (not isolated) in 45% overall yield.
Finally, 1,4-dihydroquinolines 13 and 14 were easily oxi-
dised to the respective fully aromatic heterocycles 15 and
16 in good yield.
´
Synlett 2003, 1859–1861; (d) Rosillo, M.; Domınguez, G.;
Casarrubios, L.; Amador, U.; Perez-Castells, J. J. Org.
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Chem. 2004, 69, 2084–2093; (e) Katz, J. D.; Overman, L.
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Khanye, S. D.; Aderibigbe, B. A. A.; Michael, J. P.;
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4. The Chemistry of Enamines; Rapoport, Z., Ed.; Wiley:
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5. For a recent example, see: Norton Matos, M.; Alfonso, C.
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It should be noted that, in our hands, dimethyltitano-
cene was unable to catalyse the RCM of enamides 11,
which seriously hampered the possibility of carrying
out tandem reactions from amides 9, similar to those re-
ported by Nicolaou et al. in the context of the synthesis
of cyclic enol ethers from olefinic esters.13b,c Treatment
of either acetamides 9 or enamides 11 with excess di-
methyltitanocene (2–4 mol) resulted in the formation
of complex reaction mixtures, from which only the
open-chain isomerised products 19 and 20 could be
isolated in variable yields (20–30%, Fig. 1).
7. Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa,
M. Tetrahedron 2004, 60, 3017–3035, See also Ref. 3d.
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yl)amides derived from 2-allylanilines with dimethyltit-

4038
M.-L. Bennasar et al. / Tetrahedron Letters 46 (2005) 4035–4038
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flash chromatography (hexane–AcOEt) to give the pure
enamide.
more recent work, see: (b) Yan, T.-H.; Chien, C.-T.; Tsai,
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18. An analogous mechanism had been proposed to justify the
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20. Enamide 11b: 1H NMR (CDCl3, 300 MHz) d 2.07 (d,
J = 0.8 Hz, 3H), 3.29 (d, J = 6.2Hz, 2H), 3.65 (s, 3H), 4.52
(s, 1H), 4.68 (q, J = 1.2Hz, 1H), 5.06 (m, 1H), 5.13 (m,
1H), 5.88 (m, 1H), 7.12(m, 1H), 7.20–7.30 (m, 3H); 13C
NMR (CDCl3, 75.4 MHz) d 21.8, 35.2, 52.9, 106.4, 116.4,
127.0, 127.7, 128.7, 130.0, 135.9, 137.7, 139.8, 144.1, 154.6;
HRMS calcd for C14H17NO2 + H: 231.1259. Found:
231.1338.
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2396.
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21. General procedure for the RCM step: a solution of the
appropriate enamide 11 (1 mmol) and the Grubbs catalyst
18 (0.06 mmol) in anhydrous toluene was stirred at 80 °C
under Ar for 4 h. The reaction mixture was concentrated.
The resulting residue was purified by flash chromatogra-
phy (SiO2, 9:1 hexane–AcOEt) to give the pure 1,4-
dihydroquinoline 13.
16. (a) Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1993,
4, 2085–2094; (b) Herdeis, C.; Heller, E. Tetrahedron:
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Asymmetry 1997, 8, 1115–1121; (c) Martınez, I.; Howell,
22. 1,4-Dihydroquinoline 13b: 1H NMR (CDCl3, 300 MHz) d
2.17 (m, 3H), 3.15 (d, J = 4.8 Hz, 2H), 3.80 (s, 3H), 5.52
(tq, J = 1, 1, 1, 4.8, 4.8 Hz, 1H), 7.10 (m, 2H), 7.20 (m,
1H), 7.57 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3,
75.4 MHz) d 20.1, 28.3, 52.9, 116.5, 124.3, 125.0, 125.5,
126.8, 133.0, 138.1, 139.2, 154.0.
23. For a conceptually different approach to the quinoline
system using titanium reagents, see: Macleod, C.; Austin,
C. A.; Hamprecht, D. W.; Hartley, R. C. Tetrahedron
Lett. 2004, 45, 8879–8882.
A. R. Tetrahedron Lett. 2000, 41, 5607–5611; (d) Tehrani,
K. A.; De Kimpe, N. Tetrahedron Lett. 2000, 41, 1975–
1978; (e) Langlois, N. Org. Lett. 2002, 4, 185–187.
17. General procedure for the dimethyltitanocene methylen-
ation (conditions B): a solution of freshly prepared11
Cp2TiMe2 (1 mmol) in anhydrous toluene–pyridine
(100:1, 6 mL) was added under Ar to a solution of the
appropriate amide (0.67 mmol) in anhydrous toluene
(1 mL) at rt, and the resulting mixture was stirred in