Construction of nitrogen-fused tetrahydroquinolines via a domino reaction

Article abstract of DOI:10.1021/ol3020732

An efficient domino approach for the diastereoselective synthesis of polyfunctionalized nitrogen-fused tetrahydroquinoline frameworks under mild conditions has been developed. The scope and limitation of this transformation were investigated by using a range of readily accessible enamides and benzyl azides. This method is also applicable to the formation of 2,3-functionalized enamides.

Full text of DOI:10.1021/ol3020732

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4622–4625
Construction of Nitrogen-Fused
Tetrahydroquinolines via a Domino Reaction
Nicolas Gigant and Isabelle Gillaizeau*
ꢀ
Institut de Chimie Organique et Analytique, Universite d’Orleans, UMR 7311 CNRS,
ꢀ
ꢀ
rue de Chartres, F-45067 Orleans Cedex 2, France
isabelle.gillaizeau@univ-orleans.fr
Received July 26, 2012
ABSTRACT
An efficient domino approach for the diastereoselective synthesis of polyfunctionalized nitrogen-fused tetrahydroquinoline frameworks under
mild conditions has been developed. The scope and limitation of this transformation were investigated by using a range of readily accessible
enamides and benzyl azides. This method is also applicable to the formation of 2,3-functionalized enamides.
One of the main challenges in modern organic synthesis is
to develop highly selective methodologies giving efficient and
rapid access to motifs frequently found in “privileged struc-
tures”.1 In light of these facts, diversity-oriented synthesis
(DOS) has emerged over the past decade for the preparation
of new compound libraries in order to increase their mole-
cular diversity.2 This tool is now recognized for its ability to
find new leads for potential medicinal applications and also to
highlight interactions between small molecules and macro-
molecules during the biological process. Thus, the develop-
ment of either new convenient, diversified, or step-economical
approaches can be introduced by domino reactions.3
nitrogen-fused tetrahydroquinolines,4 which were recently
referred to as privileged structures in drug discovery because
of their wide spectrum of potential biological activities.5 As
an example, this framework is present in the natural prod-
ucts martinelline acid or (þ)-martinelline6 (Figure 1). The
latter have attracted considerable attention because they are
the first naturally occurring nonpeptide bradykinin B1 and
B2 receptor antagonists and the first naturally occurring
hexahydropyrrolo[3,2-c]quinoline tricycles.
Polycyclic nitrogen-containing compounds are among
the most ubiquitous heterocycles in nature, especially
(1) (a) Thomas, G. L.; Johannes, C. W. Curr. Opin. Chem. Biol. 2011,
ꢀ
15, 516–522. (b) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–
4486. (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893–930.
(2) For recent reviews, see: (a) O’Connor, C. J.; Beckmann, H. S. G.;
Spring, D. R. Chem. Soc. Rev. 2012, 41, 4444–4456. (b) Schreiber, S. L.
Nature 2009, 457, 153–154. (c) Spandl, R. J.; Bender, A.; Spring, D. Org.
Biomol. Chem. 2008, 6, 1149–1158. (d) Burke, M. D.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2004, 43, 46–58.
(3) For recent or selected reviews, see: (a) Lu, L.-Q.; Chen, J.-R.;
Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1278. (b) Enders, D.; Grondal, C.;
Figure 1. Alkaloids containing nitrogen-fused tetrahydroquino-
line structural fragments.
€
Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (c) Tietze,
€
L. F.; Haunert, F. Stimulating Concepts in Chemistry; Vogtle, F., Stoddart,
J. F., Shibasaki, M., Ed.; Wiley-VCH: Weinheim, 2005; pp 39ꢀ64. (d)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134–7186. (e) Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
(4) For a recent review on tetrahydroquinolines, see: Sridharan, V.;
(5) (a) Miura, K.; Nishikimi, Y. WO/2008/153027, 2008. (b) Enderle,
H. WO/2008/113452, 2008. (c) Hu, Y.-J.; Tomaszewski, M.; Walpole, C.
WO/2005/075476, 2005.
ꢀ
Suryavanshi, P. A.; Menendez, J. C. Chem. Rev. 2011, 111, 7157–7259.
r
10.1021/ol3020732
Published on Web 08/22/2012
2012 American Chemical Society

Table 1. Optimization of the Domino Reaction onto Enamide 1a in the Presence of Benzyl Azide 2a
entry
equiv of 2a
acid (equiv)
solvent
timea (h)
yield 3ab (%)
yield 4ab (%)
yield 5ab (%)
1
2
1.1
1.1
1.1
1.1
3
TfOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (0.2)
TfOH (3.1)
TfOH (0.85)
TfOH (1.5)
TfOH (1.2)
TfOH (1.2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
2
48
18
0
0.25
5
14
11
3
15
0
4
5
12
24
5
2
0
0
6
0.8
1.1
1.1
1.1
1.1
1.1
1.1
2
11
22
7
2
7
trace
trace
59
8c
9d
10
11
12
2
trace
0
2
0
BF3 Et2O (1.2)
2
0
0
3
AlCl3 (1.2)
TfOH (1.2)
2
trace
trace
trace
trace
7
a Reaction time after complete reaction between benzyl azide and acid (c ≈ 0.2 mol Lꢀ1). b Yield of pure product after purification by column
3
chromatography. c Reaction mixture: c ≈ 0.067 mol Lꢀ1
.
d Reaction was carried out at ꢀ78 °C before slowly increasing the temperature up to 20 °C.
3
In our quest to generate libraries for biological screening,7
we focused our attention on the construction of nitrogen-
fused tetrahydroquinoline cores via a domino reaction
starting from benzyl azides and easily accessible enamides.
Azides are involved in a wide array of reactions especially
for the construction of new carbonꢀnitrogen bonds; they
have received much attention in recent years.8 Among these
Initially, we examined the reaction with benzyl azide 2a
(1.1 equiv) in the presence of triflic acid (1.2 equiv) in
toluene at0 °C for 15min (Table 1, entry 1). After complete
disappearance of the starting material, enamide 1a
(1 equiv) was added to the solution before stirring at room
temperature for 2 h. The reaction afforded the desired
pyrido-fused tetrahydroquinoline 3a (48% yield) and the
byproduct 4a (18% yield). The stereochemistry cis in 3a
was clearly determined by relevant 1H NOE NMR
experiments.11 However, the stereochemistry of 4a could
not be confirmed. Mechanistically, the presence of 3a and
4a derivatives could be explained as depicted in Scheme 1.
Upon protonation, benzyl azide 2a afforded intermediate
species which underwent rearrangement to form an imi-
nium ion with concomitant loss of molecular nitrogen.9
The latter was trapped by nucleophilic addition ofenamide
1a, creating the first new carbonꢀcarbon bond.12 After
subsequent cyclization onto the newly formed N-sulfony-
liminium ion via a PictetꢀSpengler reaction, the second
carbonꢀcarbon bond was performed, affording 3a as a cis
diastereoisomer. Alternatively, instead of the cyclization
step and from the N-sulfonyliminium ion, a nucleophilic
attack of a second enamide 1a could occur, leading to
derivative 4a.
ꢀ
studies, Aube and co-workers underlined an unprecedented
reactivity of benzyl azides under acidic conditions.9 They
reported the acid-promoted rearrangement of alkyl azides
providing iminium intermediates which could be trapped by
carbonyl compounds in a variant of the Mannich reaction.
Recently, Zhai’s group described the construction of a range
of tetrahydro-5H-indolo[3,2-c]quinolines via a benzyl azide-
to-iminium rearrangement followed by two sequential
PictetꢀSpengler reactions.10 Consequently, we decided to
study this alkyl azide-to-iminium rearangement in presence
of enamide for the direct construction of original nitrogen-
fused tetrahydroquinoline scaffolds.
(6) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,
A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger,
S. M.; Varga, S. L. J. Am. Chem. Soc. 1995, 117, 6682–6685.
(7) (a) Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 3304–3307. (b)
Gigant, N.; Claveau, E.; Bouyssou, P.; Gillaizeau, I. Org. Lett. 2012, 14,
844–847. (c) Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.;
Dauban, P. Chem.;Eur. J. 2012, 18, 90–94. (d) Claveau, E.; Gillaizeau,
I.; Kalinowska, J.; Bouyssou, P.; Coudert, G. J. Org. Chem. 2009, 74,
2911–2914.
Different parameters were thus investigated (Table 1).
Much lower yields were observed by modifying the reac-
tion time (entries 2 and 3), the proportion of the different
reactants (entries 4ꢀ7) or the dilution (entry 8), despite the
(8) For recent reviews on the reactivity of azides, see: (a) Driver, T. G.
€
Org. Biomol. Chem. 2010, 8, 3831–3846. (b) Brase, S.; Gil., C.; Knepper,
K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5176–5186.
(9) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan,
(11) See the Supporting Information.
(12) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292–
ꢀ
G. L.; Aube, J. J. Am. Chem. Soc. 2000, 122, 7226–7232.
(10) Song, Z.; Zhao, Y.-M.; Zhai, H. Org. Lett. 2011, 13, 6331–6333.
301.
Org. Lett., Vol. 14, No. 17, 2012
4623

Scheme 1. Plausible Mechanism for the Formation of Products
3a, 4a, 5a, and 7a
Scheme 2. Scope of the Domino Reaction by Varying
Enamides 1a,b
a Reaction conditions: 1 (1 equiv), 2 (1.1 equiv), and TfOH (1.2 equiv)
for 2 h at rt. b Yields of pure product after purification by column
chromatography.
benzoxazinic or benzothiazinic enamides, which clearly
indicates that more electron-rich enamides favored
this process. A total cis diastereoselectivity was also
observed.11
Diversification was introduced by carrying out this dom-
ino reaction with a range of benzyl azides 2in the presence of
benzoxazinic enamide 1g (Scheme 3). Screening with elec-
tron-neutral, -rich, and -poor benzyl azides was examined in
order to obtain the original heterocycles 3gꢀo, not yet
described in the literature. Pleasingly, it appears that a wide
range of benzyl azides were suitable partners for this reac-
tion; as expected, better yields were obtained with activating
groups. Low yield (3k, 23%) was obtained with a p-nitro-
substituted benzyl azide, which led to unstable iminium
species. Interestingly, when the reaction was carried out with
a meta-substituted benzyl azide, only the more congested
regioisomer 3l was isolated in 71% yield without any trace of
the sterically less congested one. A similar and total regio-
selectivity was observed starting from 2-(azidomethyl)-
naphthalene leading to the formation of a single regio-
isomer, the pentacycle 3n isolated in 63% yield. It is also
worthy of note that the reaction was successful with a
secondary benzyl azide; the fused tetrahydroquinolines 3o
was indeed furnished, albeit with low yield (32%).13 As
previously described in the literature,14 the endo-3o deriva-
tive was isolated as a single diastereoisomer.
consumption of all starting materials after 5 min. A third
product, 5a, resulting from the conjugated addition of 1a
under acidic conditions, was also isolated (Scheme 1).
By carrying out the reaction first at ꢀ78 °C and by
slowly increasing to room temperature, only 5a was iso-
lated in 59% yield (entry 9). No beneficial effect was
observed by changing the nature of the acidic source
(entries 10 and 11) or the solvent (entry 12). The use of
triflic acid seems to be crucial for the process.
Having established the optimal conditions, we next
examined the scope of this domino reaction. As shown in
Scheme 2, five-, six-, and seven-membered cyclic enamides
were investigated. It should be noted that the nature of the
electron-withdrawing N-protecting group on the starting
enamide depends only on its synthetic availability. Starting
first from the cyclic enamides 1aꢀd, the domino reaction
led in moderate yields to the following corresponding
tricyclic scaffolds: hexahydrobenzo[h][1,6]naphthyridines
3a or 3b, hexahydro-1H-pyrrolo[3,2-c]quinoline 3c, and
octahydro-1H-azepino[3,2-c]quinolin 3d.4 It should be
mentioned that for each experiment, traces of byproduct
4 or 5 (Scheme 1) were observed but not isolated. Acyclic
enamide was found to give the expected tetrahydroquino-
line core 3e in good yield. The cis relationship of the two
newly generated tertiary carbon centers was confirmed
by NMR experiments.11 Notably, excellent yields up to
85% of fused tetrahydroquinolines 3f and 3g were ob-
tained starting from the corresponding antiaromatic
In addition, we also focused on exploring C2-substituted
enamides 6 (Scheme 4). Starting from the 2-benzofuran
derivative 6a, we obtained the 2,3-difunctionalized enam-
ide 7a in quantitative yield. No trace of the previously
described C2-cyclized derivative was found. This excellent
(13) The presence of a benzylic substituent retarded the reaction and
decomposition occurred prior to the complete consumption of the
starting material.
(14) (a) Dagousset, G.; Retailleau, P.; Masson, G.; Zhu, J. Chem.;
Eur. J. 2012, 18, 5869–5873and references cited herein.
4624
Org. Lett., Vol. 14, No. 17, 2012

Scheme 3. Scope of the Domino Reaction with Varying Benzyl
Azides 2a,b
Scheme 4. Scope of the Reaction with Varying
C2-Functionalized Enamides 6a,b
a Reaction conditions: 1 (1 equiv), 2 (1.1 equiv), and TfOH (1.2 equiv)
for 2ꢀ4 h. b Yield of pure product after purification by column
chromatography.
a Reaction conditions: 1 (1 equiv), 2 (1.1 equiv), and TfOH (1.2 equiv)
for 2ꢀ4 h. b Yield of pure product after purification by column chro-
matography. c TfOH (2.4 equiv) was used.
benzyl azides. In addition, 2,3-difunctionalized enamides
bearing a β-aminomethyl side chain were also easily ob-
tained. Further studies both on the potential scope and
synthetic applications of this attractive reaction, including
acyclic enamides, are in progress in our laboratory.
result led us to consider other enamides 6 bearing different
aromatic groups at the C2 position. A series of difunctio-
nalized enamides 7aꢀf were thus synthesized with very
good to high yields. This transformation, consisting in the
acidic promoted rearrangement of benzyl azide followed
by the nucleophilic addition of enamide onto the iminium
ion intermediate, gives the opportunity to further functio-
nalize the newly synthesized disubstituted enamides, there-
by enhancing its synthetic value.
In conclusion, we have developed a simple one-pot
strategy to prepare various and eventually novel nitrogen-
fused tetrahydroquinoline scaffolds via a domino reaction.
Strikingly, this original reactivity was carried out under mild
conditions starting from readily available enamides and
ꢁ
Acknowledgment. The MESR (Ministere de l’Enseigne-
ment Superieur et de la Recherche) is gratefully acknowl-
ꢀ
edged for the doctoral fellowship to N.G.
Supporting Information Available. Full characteriza-
1
tion details including H and 13C NMR, IR, MS, and
HRMS. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4625