Concise synthesis of highly substituted benzo[a]quinolizines by a multicomponent reaction/allylation/heck reaction sequence

Article abstract of DOI:10.1002/ejoc.201101170

The combination of the recently developed multicomponent construction of highly substituted 3,4-dihydropyridones with subsequent allylation and intramolecular Heck-type cyclization allows the straightforward construction of benzo[a]quinolizines, a class of polycyclic compounds that- despite their interesting pharmacological and photochemical properties- have little precedent in the literature. After optimization of the individual steps, we used this reliable three-step sequence to generate a small library of diversely substituted benzo[a]quinolizines and various heterocyclic analogs. Copyright

Full text of DOI:10.1002/ejoc.201101170

FULL PAPER
DOI: 10.1002/ejoc.201101170
Concise Synthesis of Highly Substituted Benzo[a]quinolizines by a
Multicomponent Reaction/Allylation/Heck Reaction Sequence
René den Heeten,[a] Léon J. P. van der Boon,[a] Daniël L. J. Broere,[a] Elwin Janssen,[a]
Frans J. J. de Kanter,[a] Eelco Ruijter,*[a] and Romano V. A. Orru*[a]
Keywords: Medicinal chemistry / Multicomponent reactions / Nitrogen heterocycles / Polycyclic compounds /
Cross-coupling reactions / Palladium catalysis
The combination of the recently developed multicomponent
construction of highly substituted 3,4-dihydropyridones with
interesting pharmacological and photochemical properties –
have little precedent in the literature. After optimization of
subsequent allylation and intramolecular Heck-type cycliza- the individual steps, we used this reliable three-step se-
tion allows the straightforward construction of benzo[a]quin-
quence to generate a small library of diversely substituted
olizines, a class of polycyclic compounds that – despite their
benzo[a]quinolizines and various heterocyclic analogs.
Introduction
with isocyanide-based multicomponent follow-up chemis-
try, such as the well-known Passerini and Ugi reactions.
This approach allowed the generation of diverse com-
pounds, including small series of conformationally con-
strained depsipeptides,[7] the unprecedented dihydroox-
azolo-pyridines,[8] and highly functionalized conformation-
ally constrained peptides.[9]
Multicomponent reactions (MCRs) are highly efficient
tools for the rapid generation of molecular diversity by vir-
tue of their convergence, variability and ease of operation.[1]
Recently, the combination of MCRs with post-condensa-
tion transformations as a strategy for the preparation of
diverse arrays of unique molecular scaffolds has received
considerable attention.[2] Our group has been involved in
several projects aimed at the development of highly conver-
gent syntheses of heterocycles as privileged structures in
drug discovery. Our contribution in this field has been at-
tained, amongst others, by coupling multicomponent reac-
tions with secondary transformations. Recently, we showed
that the introduction of orthogonal functional groups in
multicomponent reactions with unique solvent and func-
tional group compatibility enables their combination with
other multicomponent reactions in one pot.[3] We also dem-
onstrated that the four-component reaction (4CR) for triaz-
inane diones[4] is a versatile platform that can be combined
with additional MCRs, ring closing metathesis, [2+3] cyclo-
addition and intramolecular Diels–Alder reactions.[5]
Scheme 1. Multicomponent reaction towards 5 and previously ex-
plored opportunities for follow-up chemistry.
In the course of our efforts to diversify 5, we demon-
strated that these compounds readily undergo N1-alkylation
after deprotonation with NaH.[9] During these reactions, we
observed that the isocyano group of 5 undergoes facile eli-
mination to give the corresponding 2-pyridones in the pres-
ence of an excess of NaH, most likely as a result of the
pseudo-antiperiplanar arrangement of the C3 isocyano
group and the C4 hydrogen. This observation prompted us
to investigate alternative possibilities for further diversifica-
tion chemistry not based on the reactivity of the isocyanide.
We opted to explore the ever-increasing potential of Pd-
catalyzed cross-coupling reactions in the further generation
of molecular diversity and complexity.[10] Thus, we envi-
sioned the N1-allylation of 5 with concomitant elimination
of the isocyanide to give 6 (Scheme 2). When R1 is an o-
bromo-(hetero)aryl substituent, 6 can undergo an intramo-
lecular Heck-type reaction to afford e.g. benzo[a]quinolizin-
In addition, we reported a 4CR of phosphonate 1, ni-
triles 2, aldehydes 3 and isocyanoesters 4 to gain access to
isocyanide-containing 3,4-dihydropyridin-2-ones
5 (3,4-
DHP-2-ones, Scheme 1).[6] The presence of the isocyanide
functionality in the MCR product allowed the combination
[a] Department of Chemistry & Pharmaceutical Sciences and
Amsterdam Institute for Molecules, Medicines & Systems, VU
University,
De Boelelaan 1083, 1081HV Amsterdam, The Netherlands
Fax: +31-20-5987488
E-mail: r.v.a.orru@vu.nl
e.ruijter@vu.nl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101170 or from
the author.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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E. Ruijter, R. V. A. Orru et al.
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4-ones 7. Fused quinolizin-4-ones have been reported to pleased to find that cyclization to give the tricyclic system
display biological activities in CNS diseases, including occurred in good yield. The intramolecular cyclization of
Alzheimer’s disease.[11]
compound 6a presumably proceeds via a 6-exo-trig route,
followed by isomerization of the exocyclic product 11 to its
endocyclic form.
Table 1. Intramolecular Heck reaction.
Scheme 2. Allylation/Heck reaction sequence for the construction
of benzo[a]quinolizines 7.
Several tandem MCR/Heck strategies have been re-
ported, but most are based on the Ugi 4CR.[12] Our proto-
col produces new and unique polycyclic compounds in a
short and efficient manner.
Entry[a] Catalyst
Base
Yield [%][b] Ratio 7/11[c]
1
Pd(OAc)2 + PPh3
Et3N
Et3N
Et3N
Et3N
Cs2CO3
Et3N
Et3N
82
79
92:8
59:41
54:46
78:22
100:0
100:0
n.d.
2
3
PdCl2 + PPh3
Pd(PPh3)4
Pd(OAc)2 + PPh3
Pd(OAc)2 + PPh3
Pd(OAc)2
75
84
4[d]
5
90
86
6
Results and Discussion
7[e]
Pd(OAc)2 + PPh3
Ͻ 20
We previously showed that DHP-2-ones 5 are readily N-
alkylated using activated alkyl halides.[9] Using the same
procedure, compound 5a (R1 = o-BrC6H4, R2 = R3 = Ph)
was allylated with allyl bromide after deprotonation of the
amide with stoichiometric amounts of NaH to give 8a in
good yield (77%).
As mentioned above, the DHP-2-one isocyano group is
readily eliminated under basic conditions. We envisioned
obtaining N-allylated 2-pyridones 6 in a one-pot procedure
starting from DHP-2-ones 5 using an excess of NaH
(Scheme 3). Indeed, the desired N-allylation product 6a was
isolated in 72% yield and none of the corresponding O-
allylation product 9a was observed.
[a] Conditions: 5 mol-% Pd, 10 mol-% L, 2.0 equiv. base, DMF,
120 °C, 16 h. [b] Isolated yield. [c] Determined by H NMR spec-
troscopy. [d] NMP used as solvent. [e] 1 mol-% Pd, 2 mol-% L.
1
All of the tested conditions promoted the cyclization of
6a with high conversions, but the degree of isomerization
varied depending on the palladium source (Table 1, entries
1–3). Large amounts of the exocyclic isomer 11 were ob-
served when Pd(PPh3)4 was used as catalyst (entry 3). The
base used did not influence the conversion much (entries 4
and 5). The reaction proceeded both with good conversion
and with full selectivity for the desired product 7a in the
absence of a phosphane ligand (entry 6). Thus, the “li-
gandless” protocol using Pd(OAc)2 as the palladium source
in combination with Et3N as a base was selected as the
most effective and practical method to obtain compound
7a selectively.
With a general method for the rapid construction of
benzo[a]quinolizines 7 in hand, we set out to investigate the
scope of our methodology. From our previous studies, it
had become clear that the phosphonate component showed
limited variation possibilities.[13] The best results were ob-
tained using diethyl methylphosphonate 1, and the current
experiments were therefore performed using this compo-
nent. Various nitriles 2, aldehydes 3, and isocyano esters 4
were tested (Figure 1). The (racemic) isocyano esters 4 are
readily available in three steps from the corresponding
amino acids using a procedure recently described by us.[14]
All nitriles and aldehydes used were either commercially
available or were readily obtained via short and efficient
synthetic routes (for details, see Supporting Information).
The one-pot reaction of 1 and various nitriles, aldehydes,
and aromatic isocyano esters is presented in Table 2. In ge-
neral, DHP-2-ones 5a–5t were prepared by following the
Scheme 3. Allylation of DHP-2-one 5a.
The next task at hand was the intramolecular Heck-type reported procedure[6] using 1.05 equiv. of nBuLi[15] and
cross-coupling reaction of 6a. In our initial attempt of the 1.1 equiv. of the appropriate nitrile, aldehyde and isocyano
key intramolecular Heck reaction [5 mol-% Pd(OAc)2, ester. In all examples, a complete selectivity towards the 3,4-
10 mol-% PPh3, 120 °C, 16 h; Table 1, entry 1], we were cis-diastereomer of 5 was observed.
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Concise Synthesis of Highly Substituted Benzo[a]quinolizines
reason, 4b (R3 = p-chlorophenyl, entry 19) also gave good
results.[6] Several aromatic nitriles containing electron-do-
nating or electron-withdrawing groups were evaluated as re-
action partner in the 4CR (entries 2–8). Whereas nitriles 2e,
2g and 2h led to the corresponding DHP-2-ones 5 in good
yields, no product formation was observed in the reactions
with nitriles 2b, 2c and 2d. In addition, nicotinonitrile 2f
(entry 6) failed to provide the 3,4-dihydropyridin-2-one 5f.
Aromatic and heteroaromatic aldehydes gave the expected
3,4-DHP-2-ones in reasonable to excellent yields (entries
13–17). The reaction using highly electron-deficient p-ni-
trobenzaldehyde 3g presents an exception and leads directly
to 2-pyridone 8r. The proton adjacent to the isocyanide
functionality in the initially formed DHP-2-one 5r is highly
acidic (due to the adjacent p-nitrophenyl group) and is
likely abstracted under the basic reaction conditions. Sub-
sequently, the isocyanide group in DHP-2-one 5r is elimin-
ated in situ to give 10r (Scheme 4).
Figure 1. The various nitriles 2, aldehydes 3 and isocyano esters 4
used in the DHP-2-one 4CR.
Table 2. One-pot reaction between phosphonate 1 and various ni-
triles 2, aldehydes 3, and isocyano esters 4.[a]
Scheme 4. Formation of 2-pyridone 10r.
Entry
Nitrile Aldehyde Isocyano ester Product Yield [%][b,c]
For the synthesis of a benzothiophene containing DHP-
2-one we first explored the use of hydroxy-protected benzo-
thiophene 2j. 3-Hydroxy-1-benzothiophene-2-carbonitrile is
efficiently synthesized in large quantities from readily avail-
able, cheap starting materials.[16] The triflate protected de-
rivative 2j can be used in our envisioned sequence towards
polycyclic compounds 7 since triflates are good reaction
partners in Heck reactions. Unfortunately, the correspond-
ing DHP-2-one 5j was not formed. Plausibly, the O-triflyl
group migrated to the nitrogen atom of the intermediate
imide 12 leading to the formation of sulfonimide 13
(Scheme 5). This would hamper the formation of the 1-aza-
diene intermediate and, consequently, the formation of
5j.[17] The use of bromobenzothiophene derivative 2l as the
nitrile component in the 4CR did result in the formation of
DHP-2-one 5l, albeit in low yield (see entry 12 in Table 2).
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4a
5a
5b
5c
5d
5e
86
0
0
0
81
0
61
74
38
0
5f
2g
2h
2i
5g
5h
5i
9
10
11
12
13
14
15
16
17
18
19
20
2j
5j
2k
2l
5k
5l
0
29
88
75
58
86
87
95
53
66
2a
2a
2a
2a
2a
2a
2a
2e
5m
5n
5o
5p
5q
10r[d]
5s
3g
3a
3c
5t
[a] All reactions were carried out using 0.2 m phosphonate,
1.05 equiv. of nBuLi, 1.1 equiv. of nitrile, aldehyde, and isocyano
ester. For the structures of 2a–l, 3a–g and 4a,b, see Figure 1. [b]
Isolated yields. [c] Only the 3,4-cis-diastereomer was observed in
the 1H NMR of the crude product. [d] The expected DHP-2-one
5r was not isolated but immediately leads to pyridine-2-one 10r (see
Scheme 4 and text).
Scheme 5. Putative triflyl migration in the 4CR using 2j.
The majority of the above experiments were performed
Next, we turned our attention to the tandem N-all-
using isocyano ester 4a, which is an excellent reaction part- ylation/isocyanide elimination of MCR products 5a–t. In
ner in the 4CR because of its high α-acidity. For the same general the desired products 6 were obtained in moderate
Eur. J. Org. Chem. 2012, 275–280
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277

E. Ruijter, R. V. A. Orru et al.
FULL PAPER
to good yields (31–78%, Figure 2). However, when sub-
strates 5p–r containing an electron-withdrawing R2 substit-
uent were used, the O-allylated derivatives 9p and 9r were
the main products. Compounds 6 and 9 were readily sepa-
rated by column chromatography. For 6q, the isolation
proved to be troublesome and a two-pot procedure, i.e. iso-
cyanide elimination followed by N-allylation, was necessary
to achieve acceptable isolated yields (see Supporting Infor-
mation). Compound 6u was readily obtained by reaction of
5a with cinnamyl bromide.
Figure 3. Synthesis of polycyclic compounds 7a–u by intramolecu-
lar Heck reaction (yields in parentheses). Reagents and conditions:
6, Pd(OAc)2 (5 mol-%), Et3N (2.0 equiv.), DMF, 120 °C, 16 h.
The intramolecular Heck coupling products 7a–u were
obtained in moderate to very good yield (30–94%). In cases
involving electron-rich aryl bromides (7e, 7t) or heteroaryl
bromides (7i, 7l) the yields were significantly below average
(30–41%). Moderate yields were observed for compounds
bearing a highly electron-rich (7n) or electron-deficient (7q,
7r) aryl group at the 4-position of the pyridone ring (37–
58%). The remaining benzo[a]quinolizines were typically
obtained in good to excellent yield.
Figure 2. Tandem N-allylation/isocyanide elimination products 6
(isolated yields in parentheses). Reagents and conditions: 5, NaH
(3.0 equiv.), allyl bromide (or cinnamyl bromide for 6u), THF,
50 °C.
Several of the resulting polycyclic scaffold structures bear
Using the optimized conditions (Table 1, entry 6) we direct resemblance to medicinally relevant compounds.
were able to synthesize a small library of fifteen polycyclic Benzothiophene-fused compound such as 7l resemble com-
compounds 7a–u (Figure 3). In many cases, the product pounds active in CNS disease.[11] On the other hand, di-
precipitated from the reaction mixture upon cooling to am- methoxyisoquinoline-fused structures similar to 7e and 7t
bient temperature.
are found in the protoberberine class of naturally occurring
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Concise Synthesis of Highly Substituted Benzo[a]quinolizines
alkaloids,[18,19] compounds with various biological activities
including anticancer activity.[20]
–78 °C for 45 min, at –40 °C for 1 h and at –5 °C for 30 min. The
aldehyde (1.1 equiv.) was added and, after stirring at –5 °C for
30 min, the mixture was warmed to room temp. and stirred for
1.5 h. Finally the isocyanoacetate (1.1 equiv.) was added and the
mixture was stirred overnight at room temperature. The reaction
mixture was concentrated in vacuo and the crude product purified
by column chromatography.
In addition to the possible relevance of compounds 7 in
a pharmaceutical context, we noticed their remarkable fluo-
rescent properties. All compounds 7a–u are yellow/green
colored and display bright blue fluorescence without appar-
ent influence of the substitution pattern on the fluorescence
wavelength. We measured absorption and emission spectra
for compounds 7a, 7g, and 7t. All three compounds dis-
played two absorption maxima in the visible region, one at
412–418 nm and a second at 435–440 nm, with reasonable
extinction coefficients (ε = 1.5ϫ104 m–1 cm–1 for all three
compounds). These compounds all displayed broad emis-
sion peaks with maxima in the range of 485–487 nm regard-
less of the irradiation wavelength (see Figure 4 for the spec-
tra of 7a). Remarkably, the absorption and emission max-
ima seem fully independent of the substitution pattern.
General Procedure for N-Allylation/Elimination of DHP-2-ones: To
a mixture of NaH (60 wt.-% in mineral oil, 3 equiv.) in dry THF
was added dropwise a solution of DHP-2-one 5 (1 equiv.) in THF
at 0 °C. Next, allyl bromide or cinnamyl bromide (1.2 equiv.) was
added. The resulting mixture was left to stir for 16 h at 50 °C. The
reaction mixture was poured over ice water and extracted twice
with EtOAc. The combined organic phases were dried with
MgSO4, concentrated under reduced pressure and the crude prod-
uct was purified by column chromatography.
General Procedure for Heck Reaction: A solution of compound 6
(1.0 equiv.), Pd(OAc)2 (5 mol-%), PPh3 (10 mol-% if applicable)
and base (2.0 equiv.) in dry DMF was stirred at 120 °C for 16 h.
After cooling to room temperature, the reaction mixture was
quenched with water and extracted twice with EtOAc. The com-
bined organic phases were dried with MgSO4 and concentracted
under reduced pressure. The crude product was purified by column
chromatography or by recrystallization from EtOAc/Et2O mixtures.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data and
1
copies of H and 13C NMR spectra for all new compounds.
Acknowledgments
We thank Dr. M. T. Smoluch for (HR)MS measurements and Mr.
R. M. P. Veenboer for UV/Vis and fluorescence spectroscopy mea-
surements. This work was financially supported by the Netherlands
Organization for Scientific Research (NWO) by means of a Vici
grant to R. V. A. O.
Figure 4. Normalized absorption and emission spectra of com-
pound 7a (absorption in black, emission in grey). Compounds 7g
and 7t display almost identical absorption and emission spectra.
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Conclusions
In conclusion, we have developed a new method for the
synthesis of functionalized polycyclic structural chemo-
types. Access to the tricyclic benzo[a]quinolizine ring sys-
tem and various heterocyclic analogs is readily provided by
a straightforward three-step reaction sequence. The 3,4-
DHP-2-one 4CR is combined with post-condensation
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Experimental Section
General Procedure for Multicomponent Synthesis of DHP-2-ones:
All reactions were carried out at a concentration of 0.2 m of phos-
phonate 1, 0.21 m of nBuLi, 0.22 m of nitrile 2, 0.22 m of aldehyde
3 and 0.22 m of isocyanoacetate 4 in dry THF. To a stirred solution
of phosphonate in THF was added nBuLi (1.6 m solution in hex-
ane, 1.05 equiv.) at –78 °C After stirring at –78 °C for 1.5 h the
nitrile (1.1 equiv.) was added and the mixture was then stirred at
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Received: August 9, 2011
Published Online: September 28, 2011
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