An intramolecular C-N cross-coupling of β-enaminones: A simple and efficient way to precursors of some alkaloids of Galipea officinalis

Article abstract of DOI:10.3762/bjoc.11.99

2-Aroylmethylidene-1,2,3,4-tetrahydroquinolines with the appropriate substituents can be suitable precursors for the synthesis of alkaloids from Galipea officinalis (cuspareine, galipeine, galipinine, angustureine). However, only two, rather low-yielding procedures for their synthesis are described in the literature. We have developed a simple and efficient protocol for an intramolecular, palladium or copper-catalysed amination of both chloro- and bromo-substituted 3-amino-1,5-diphenylpent-2-en-1-ones leading to the above-mentioned tetrahydroquinoline moiety. The methodology is superior to the methods published to date.

Full text of DOI:10.3762/bjoc.11.99

An intramolecular C–N cross-coupling of β-enaminones: a
simple and efficient way to precursors of some alkaloids of
Galipea officinalis
Hana Doušová1, Radim Horák1, Zdeňka Růžičková2 and Petr Šimůnek*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 884–892.
1Institute of Organic Chemistry and Technology, Faculty of Chemical
Technology, University of Pardubice, Studentská 573, CZ 532 10,
Pardubice, Czech Republic and 2Department of General and
Inorganic Chemistry, Faculty of Chemical Technology, University of
Pardubice, Studentská 573, CZ 532 10, Pardubice, Czech Republic
doi:10.3762/bjoc.11.99
Received: 17 February 2015
Accepted: 22 April 2015
Published: 27 May 2015
Email:
Associate Editor: I. Marek
Petr Šimůnek* - petr.simunek@upce.cz
© 2015 Doušová et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
C–N cross-coupling; copper; enaminone; palladium;
tetrahydroquinoline
Abstract
2-Aroylmethylidene-1,2,3,4-tetrahydroquinolines with the appropriate substituents can be suitable precursors for the synthesis of
alkaloids from Galipea officinalis (cuspareine, galipeine, galipinine, angustureine). However, only two, rather low-yielding pro-
cedures for their synthesis are described in the literature. We have developed a simple and efficient protocol for an intramolecular,
palladium or copper-catalysed amination of both chloro- and bromo-substituted 3-amino-1,5-diphenylpent-2-en-1-ones leading to
the above-mentioned tetrahydroquinoline moiety. The methodology is superior to the methods published to date.
Introduction
Galipea officinalis Hancock is a Venezuelan shrub, the bark
(angostura bark) of which is used in folk medicine for stimula-
tion in the cure of some paralytic diseases [1] and for the treat-
ment of fever [2]. In addition, antituberculous [3], antiplas-
modial and cytotoxic [2] properties have been also described.
The active constituents of the bark are mainly tetrahydroquino-
line alkaloids such as galipinine, galipeine, cuspareine and
angustureine (Figure 1) [1,4].
The synthesis of these alkaloids has attracted great interest in
Figure 1: Tetrahydroquinoline alkaloids of Galipea officinalis.
organic chemists and many procedures have been published to
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Beilstein J. Org. Chem. 2015, 11, 884–892.
date [5-30]. As part of our ongoing interest in the preparation of The synthesis of ester 5 was accomplished according to
polarized ethylenes and their application in organic synthesis, Scheme 4. The classic Knoevenagel/reduction/hydrolysis/decar-
we have been attracted by the procedure published by Zhou boxylation pathway (steps a–d in Scheme 4) to carboxylic acid
[30]. Here, the authors used heterocyclic enaminone 1b as the 10 suffered from low yields of the last two steps (total yield
reactant for an asymmetric reduction followed by N-methyl- 33%). The attempt to obtain 5a directly from 9 by means of
ation to give (S)-cuspareine in high yields and excellent stereo- Krapcho decarboxylation [33] failed, as the product was conta-
selectivity (Scheme 1).
minated with inseparable byproducts. A better and less time-
consuming route to 10 consists of the reaction of 2-halobenzal-
This method, however, suffers from a low-yielding (28%) syn- dehyde 7 with Meldrum´s acid in the presence of HCOOH/Et3N
thesis of the enaminone 1a [30]. Only two methods for the syn- system with a total yield of 61–67% (step f in Scheme 4). The
thesis of tetrahydroquinolines 1 have been described in the last step for both methods was the esterification of acids 10a,b
literature [30-32] based on a catalytic hydrogenation of the (step e in Scheme 4).
corresponding quinolones 2 (Scheme 2) with yields not greater
than 43%. In the present work, we introduce a quite different β-Diketones 4 were obtained using tert-butoxide or tert-
approach to the exocyclic enaminones 1 based on an intramole- pentoxide mediated Claisen condensation of esters 5 with the
cular C–N cross-coupling of enaminones 3 (Scheme 2).
appropriate acetophenones 6a–d (Scheme 5, step c). The substi-
tution pattern on compounds 6 was chosen so that the final
products 1 are the precursors for the synthesis of galipinine,
galipeine and angustureine (Figure 1). 3-Hydroxy-4-methoxy-
Results and Discussion
The synthesis of the starting substrates
A simple retrosynthesis of enaminones 3 leads to the corres- acetophenone (6e) was prepared by selective deprotection of
ponding β-diketones 4 accessible through Claisen condensation commercially available 3,4-dimethoxyacetophenone (6b) [34]
of 3-phenylpropionic ester 5 with the appropriate acetophenone (Scheme 5, step a). The hydroxy group in 6e was then protected
6 (Scheme 3).
with a benzyl group (step b). The final step d was the reaction
Scheme 1: Enaminone-based synthesis of (S)-cuspareine.
Scheme 2: The approaches to 2-aroylmethylidene-1,2,3,4-tetrahydroquinolines 1.
Scheme 3: The retrosynthetic analysis of the starting substrates for C–N cross-coupling.
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Beilstein J. Org. Chem. 2015, 11, 884–892.
Scheme 4: The synthesis of methyl 3-phenylpropionates. Conditions: (a) piperidine, PhCOOH, toluene, reflux 4 h; (b) NaBH4, MeOH/MeCN, rt, 3.5 h;
(c) KOH, H2O, reflux, 8 h; (d) H2SO4, H2O, reflux, 20 h; (e) MeOH, SOCl2, reflux, 4 h; (f) Meldum’s acid, HCOOH, Et3N, 100 °C, 4 h.
Scheme 5: The synthesis of the starting β-enaminones. Conditions: (a) H2SO4, 65 °C, 46 h; (b) 1. t-BuOK/THF, rt, 30 min, 2. BnBr, reflux 5 h;
(c) t-BuOK, t-BuONa or t-AmOK, THF, rt overnight; (d) AcONH4, MeOH, reflux 5 h (NH4HCO3, MeOH/THF, rt 24 h for 3d).
of β-diketones 4 with ammonium surrogate (AcONH4 or with the relatively high chemical shift of one resonance of the
NH4HCO3). The regioselectivity of the synthesis was checked pair (δ ≈ 10 ppm) indicates the presence of an intramolecular
by means of 2D 1H–13C HMBC (See Supporting Information hydrogen bond N–H···O. The enaminones 3 therefore possess Z
File 1, page S69). The non-equivalence of NH2 protons together configuration on the C=C bond.
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Beilstein J. Org. Chem. 2015, 11, 884–892.
The intramolecular C–N cross-coupling
Rather, a higher amount of palladium was necessary for
β-Enaminones and related polarized ethylenes (generally completing the reaction in a short reaction time (Table 1, entry
enamines substituted by EWG on β-carbon atom) belong among 3). Switching to the bidentate ligand L5 (Figure 2) gave compa-
the rather neglected molecules from a C–N cross-coupling rable conversion but over a substantially longer period (Table 1,
perspective. There are relatively few works (about ten) dealing entry 4). Buchwald et al. [47] described a protocol for genera-
with these very useful molecules [35-46], in comparison to the tion of the highly active Pd(0) catalyst from Pd(OAc)2 using
hundreds of papers dedicated to the other substrates. Due to water-mediated pre-activation. However, no conversion was
their electronic nature, β-enaminones can be considered vinylo- observed here for L1 (Table 1, entry 5).
gous amides. Hence, their nucleophilicity is lowered and
enaminones can be more challenging substrates for C–N cross- Besides palladium, copper is another widely applied metal for
coupling compared to ordinary enamines.
C–N bond formation [50-52]. We then applied the CuI/[L]
catalytic system to 3a (see method C in Supporting Information
We used 3a as the model substrate for the optimization study. File 1, pages S25 and S26). The choice of the ligand is crucial
The reaction conditions were surveyed from the following here, as L7 (Figure 2) had no effect (Table 1, entry 6) whereas
aspects: catalytic system [M]/[L] and base (Table 1).
using another common ligand L8 (Figure 2) led to the full
conversion to 1a (Table 1, entry 7). Caesium carbonate was the
We used tris(dibenzylideneacetone)dipalladium(0) as the optimal base as neither K2CO3 nor K3PO4 gave satisfactory
starting palladium source. To suppress the problems with the results (Table 1, entries 8 and 9).
attenuation of its catalytic activity due to the coordination of
dba ligands to the central metal, we applied preheating of From the above-mentioned facts, summarized in Table 1, it
Pd2(dba)3 with the corresponding ligand [L] to generate the follows that the optimal results were obtained using catalytic
active catalyst [48] prior to the addition to substrate 3 (see systems Pd2(dba)3/L1 (Table 1, entry 3) or CuI/L8 (Table 1,
Method A in the Experimental). Dialkylbiarylphosphines entry 7) in toluene with caesium carbonate as the base. We
currently belong among the most common ligands for palla- further preferred the first one (Table 1, entry 3) both due to the
dium-catalyzed C–N cross-coupling [48,49]. The use of L1 lower amount of the catalyst and shorter reaction time. Never-
(Figure 2) in combination with Pd2(dba)3 in toluene led to the theless, the copper-mediated variant could be interesting for
successful formation of product 1a (Table 1, entries 1–3). preparations on a larger scale.
Table 1: Optimisation study for C–N cross-coupling of bromo derivatives.
Entry
[M]/%
[L]/%a
Base/equiv
Time/h
Conversionb
1c
2c
3c
4c
5d
6e
7e
8e
9e
Pd2(dba)3/2.5
Pd2(dba)3/2.5
Pd2(dba)3/3.5
Pd2(dba)3/3.5
Pd(OAc)2/5
CuI/10
L1/5
Cs2CO3/1.6
Cs2CO3/1.6
Cs2CO3/1.4
Cs2CO3/1.4
Cs2CO3/1.4
Cs2CO3/1.4
Cs2CO3/1.4
K3PO4/2
3
87
L1/5
18
2
87
L1/7
94 (92)
L5/7
17
21
18
18
20
20
96 (88)
L1/15
L7/20
L8/20
L8/20
L8/20
0
0
CuI/10
>99 (83)
CuI/10
12
0
CuI/10
K2CO3/2
aFor ligands see Figure 2. bConversion determined by means of 1H NMR. Isolated yields in parentheses. cMethod A (See Experimental and
Supporting Information File 1). dMethod B. Water-mediated pre-activation used [47]. (See Supporting Information File 1). eMethod C. (See Supporting
Information File 1).
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Beilstein J. Org. Chem. 2015, 11, 884–892.
Figure 2: Ligands for C–N cross-coupling used in this work.
With the conditions chosen for the bromo derivatives, we turned entry 1). Changing the ligand to DavePhos (L3) or BINAP (L5)
our attention to the chloro derivatives. As chloro derivatives are (Figure 2) did not improve the situation at all (Table 2, entries 2
more challenging substrates for cross-coupling reactions, we and 3). The application of a palladacycle-based pre-catalyst L6
started with the successful catalytic system (Table 1, entry 3) (Figure 2) (see method D in Supporting Information File 1,
but with an increased amount of palladium, applied to 3e as the pages S25 and S26), introduced by Buchwald et al. [53] failed
model substrate. However these conditions failed (Table 2, as well (Table 2, entries 4–6). The sterically more demanding
Table 2: Optimisation study for C–N cross-coupling of chloro derivatives.
Entry
[Pd]/%
[L]/%a
Solvent
Time/h
Conversion/%b
1c
Pd2(dba)3/5
Pd2(dba)3/5
Pd2(dba)3/5
L6/3
L1/10
L3/10
L5/10
toluene
toluene
toluene
toluene
DMF
48
24
48
24
24
24
22
22
17
24
24
0
2c
0
3c
0
4d,e
5d,e
6d,e
7c
0
L6/3
4
L6/3
t-AmOH
toluene
toluene
t-AmOH
t-AmOH
toluene
0
Pd2(dba)3/5
Pd2(dba)3/5
Pd2(dba)3/5
Pd2(dba)3/2.5
CuI/10
L4/10
L2/10
L2/10
L5/5
29
8c
64
9c
100 (72)f
10c
11g
47
0
L7/20
aFor ligands see Figure 2. bConversion determined by means of 1H NMR. Isolated yields in parentheses. cMethod A. dMethod D. eTwo equivalents of
the base used. fIsolated yield. gMethod C.
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Beilstein J. Org. Chem. 2015, 11, 884–892.
ligand BrettPhos (L4, Figure 2), reported as a very effective protocol was quite unsuccessful (Table 2, entry 11). Generally,
ligand for N-arylations of primary amino groups [48,54], chloro derivatives (and especially non-activated ones) remain
worked better but was still not satisfactory (Table 2, entry 7). challenging substrates for copper catalysis [50]. The conditions
The breakthrough was made after applying t-BuXPhos (L2, in Table 2, entry 9 (5 mol % Pd2(dba)3, 10 mol % t-BuXPhos,
Figure 2), which led to 64% conversion (Table 2, entry 8). Cs2CO3 in t-AmOH) were thus the best for the cyclization of
Switching from toluene to t-AmOH finally led to full conver- chloro derivatives.
sion to the desired product (Table 2, entry 9). An attempt to
reduce the amount of catalyst, however, only led to a decrease These conditions, however, did not work for the bromo deriva-
in the conversion (Table 2, entry 10). The copper-catalyzed tives, despite the higher amount of both palladium and ligand
Table 3: The intramolecular C–N cross-coupling of enaminones 3: a summary of results.
Producta
Reactant General procedureb
Solvent
[L]
Base
Yield[%]/Conv.[%]
A
C
toluene
toluene
L1
L8
Cs2CO3
Cs2CO3
92
83
3a
3e
Ac
t-AmOH L2
Cs2CO3
72
(p. S27)
A
A
A
B
toluene
toluene
toluene
toluene
L1
L1
L1
L1
Cs2CO3
K2CO3
K3PO4
65
/29
/0
3b
3f
Cs2CO3
/0
A
t-AmOH L2
Cs2CO3
72
(p. S28)
3c
3g
Ad
A
toluene
L1
Cs2CO3
Cs2CO3
85/50e
82
t-AmOH L2
(p. S29)
3d
3h
A
A
toluene
L1
Cs2CO3
Cs2CO3
45
61
t-AmOH L2
(p. S30)
aSee Supporting Information File 1 for details. bFor procedures see Supporting Information File 1 p. S25 (methods A,B) or p. S26 (methods C,D). cFor
2.5 mol % Pd2(dba)3, 5 mol % L2 conversion 47%. d5 mol % of Pd2(dba)3 and 10 mol % L1 used. eConversion for 3.5 mol % of Pd2(dba)3 and
7 mol % L1.
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and a substantially longer reaction time. Compound 3b was
transformed into 1b using the above-mentioned conditions
(Table 2, entry 9) only in 20% conversion.
Having the conditions for the successful cyclization of
enaminones 3a,e to tetrahydroquinoline 1a in hand, we applied
them to other enaminones 3. In all of these cases, the corres-
ponding tetrahydroquinolines 1 were obtained in moderate to
high yields (Table 3).
The deprotection of the hydroxy group in 1c was accomplished
using BCl3 in DCM (Figure 3) to obtain the precursor 1e for
galipeine (Figure 1).
Figure 4: ORTEP (50% probability level) view for compound 1a. For
selected parameters see Supporting Information File 1.
On the basis of relatively high chemical shifts of NH protons in
compounds 1 (δ > 12), it can be assumed that all of these com-
pounds have Z configuration on the C=C double bond (in-
creased chemical shifts due to the presence of an intramolec- established a novel, simple protocol for the synthesis of the
ular hydrogen bond C=O···H–N). This assumption was above-mentioned 2-aroylmethylidene-1,2,3,4-tetrahydroquino-
confirmed by means of X-ray characterization of the compound lines, which is superior to the methods published so far. The
1a (Figure 4).
methodology is based on an intramolecular C–N cross-coupling
of acyclic β-enaminones. The reaction conditions are described
According to the literature [55], as well as the Cambridge Struc- for the successful cyclization of both bromo and chloro deriva-
tural Database, there is a plethora of compounds with an tives. The crucial factors here are the ligand and the solvent.
intramolecular N–H···O=C contact like 1a; on the other hand, The best system for bromo derivatives is Pd2(dba)3/XPhos/
the family of structurally related 1,2-dihydroquinolines [56] and Cs2CO3 in toluene, although the transformation is also feasible
ethanones [57] is limited to only seven examples. In the struc- using CuI/DESA/Cs2CO3 in toluene, albeit for a substantially
ture of 1a, some extent of π-electron delocalization is reflected longer time than in the palladium-catalyzed version. The more
in slight shortening of the formal single bond between C1 and challenging chloro derivatives required higher amounts of palla-
C2 atoms, on the contrary to a slight elongation of C2–C3 and dium, different ligands and solvents, together with much longer
C1–O1 distances – formally the double bonds (for crystal data reaction times. Pd2(dba)3/t-BuXPhos/Cs2CO3 in t-AmOH
see Supporting Information File 1, pages S27 and S28), simi- worked best. Due to the importance of polarized ethylenes, the
larly to the situation found for peptide type of bonding [55].
extension of the methodology to other substrates and
substituents could be useful and is the subject of thorough
examination nowadays.
Conclusion
An asymmetric reduction of suitably substituted 2-aroylmethyli-
dene-1,2,3,4-tetrahydroquinolines is one of the possible routes Experimental
to tetrahydroquinoline alkaloids of Galipea officinalis. The For analytical and synthetic procedures as well as characteriza-
methodology, however, suffered from the unsatisfactory source tion data of individual compounds and copies of their NMR
of the 2-aroylmethylidene reactants. In this work, we have spectra see Supporting Information File 1.
Figure 3: Deprotection of the hydroxy group in 1c to give the Galipein precursor 1e.
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Beilstein J. Org. Chem. 2015, 11, 884–892.
Representative procedure for palladium-
catalyzed synthesis of tetrahydroquinolines
1a–d (Method A)
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An oven-dried vial equipped with a magnetic stir bar and fitted
with a Teflon septum was charged with Pd2(dba)3 and the
corresponding ligand. The vessel was evacuated three times and
backfilled with argon. Subsequently, the solvent (3 mL) was
added via a syringe and the mixture was preheated at 100 °C for
30 min. Another oven-dried vial was charged with Cs2CO3 and
substrate 3. Also, this vessel was evacuated three times and
backfilled with argon. The solution of the activated catalyst was
transferred from the first vial into the second one via a syringe.
The vessel was then heated at 100 °C until the starting compo-
nent was fully consumed (control by TLC). The mixture was
then diluted with EtOAc and filtered through a small plug of
Celite® S which was subsequently thoroughly washed with
EtOAc. The filtrate was concentrated in vacuo and the residue
was purified by recrystallization or column chromatography
(see details at individual compounds).
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12.85 (brs, 1H), 7.94–7.91 (m, 2H), 7.50–7.42 (m, 3H),
7.21–7.17 (m, 1H), 7.12–7.10 (m, 1H), 6.99–6.94 (m, 2H), 5.88
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(100.62 MHz) δ 189.7, 159.0, 139.9, 136.7, 131.3, 128.5, 128.4,
127.9, 127.3, 125.3, 123.3, 116.8, 92.6, 28.8, 24.4 ppm.
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Supporting Information
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Supporting Information File 1
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Experimental procedures, characterization data and copies
of NMR spectra.
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Tetrahedron: Asymmetry 2005, 16, 827–831.
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Acknowledgements
H.D. and P.Š. thank the University of Pardubice, Faculty of
25.Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.;
Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc. 2011, 133,
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Chemical Technology for the institutional support.
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