General and efficient organocatalytic synthesis of indoloquinolizidines, pyridoquinazolines and quinazolinones through a one-pot domino michael addition-cyclization-pictet-spengler or 1,2-amine addition reaction

Article abstract of DOI:10.1002/adsc.201100258

An asymmetric organocatalyzed reaction sequence involving a Michael addition of various 1,3-dicarbonyl compounds to α,β-unsaturated aldehydes with subsequent diastereoselective Pictet-Spengler cyclization has been developed. The substrate scope was found to be general and optically active indoloquinolizidines were isolated as single diastereomers in high yields with high to excellent enantioselectivites. In addition to tryptamine, the reaction has also been successfully applied to other nucleophiles including o-aminobenzylamine and anthranilamide giving rise to pyridoquinauolines and quinazolinones. Copyright

Full text of DOI:10.1002/adsc.201100258

FULL PAPERS
DOI: 10.1002/adsc.201100258
General and Efficient Organocatalytic Synthesis of
Indoloquinolizidines, Pyridoquinazolines and Quinazolinones
through a One-Pot Domino Michael Addition-Cyclization-
Pictet–Spengler or 1,2-Amine Addition Reaction
Magnus Rueping,a,* Chandra M. R. Volla,a Michael Bolte,b and Gerhard Raabea
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2665; phone: (+49)-241-809-4710; e-mail: magnus.rueping@rwth-aachen.de
Department of Inorganic and Analytical Chemistry, Goethe University, Max-von-Laue Strasse 7, 60438 Frankfurt am
b
Main, Germany
Received: April 6, 2011; Revised: June 14, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100258.
Abstract: An asymmetric organocatalyzed reaction vites. In addition to tryptamine, the reaction has also
sequence involving a Michael addition of various 1,3- been successfully applied to other nucleophiles in-
dicarbonyl compounds to a,b-unsaturated aldehydes cluding o-aminobenzylamine and anthranilamide
with subsequent diastereoselective Pictet–Spengler giving rise to pyridoquinauolines and quinazolinones.
cyclization has been developed. The substrate scope
was found to be general and optically active indolo- Keywords: Brønsted acids; diarylprolinol ethers;
quinolizidines were isolated as single diastereomers Lewis base catalyis; Mannich reaction; multicompo-
in high yields with high to excellent enantioselecti- nent reaction
Introduction
We have previously reported a general and practi-
cal enantioselective organocatalytic addition-cycliza-
The indoloquinolizidine skeleton is a common struc- tion cascade of 1,3-dicarbonyl compounds to a,b-un-
tural motif, found in a wide range of naturally occur- saturated aldehydes.[9] In the presence of a catalytic
ring indole alkaloids.[1,2] These compounds have at- amount of diarylprolinol ether as Lewis base, dike-
tracted great attention due to their various biological tone 1 reacted with unsaturated aldehydes 2 to give
and medicinal properties[3] and several methods are chromenones 3.[9c] We now report our full studies em-
now available for the construction of their key struc- ploying this strategy in the first fast and efficient syn-
tural unit. However, most of the developed methods thesis of indoloquinolizidines, pyridoquinazolines and
involve multiple steps and are generally based on the quinazolinones.
chiral pool approach.[4] Recently, Franzꢀn and co-
We envisioned that subsequent to the formation of
workers reported an organocatalytic reaction cascade chromenone 3, a Brønsted acid-catalyzed reaction of
for the synthesis of quinolizidine derivatives.[5] The the hemiacetal with tryptamine (4) generates the imi-
demand for the development of new and efficient nium ion 5. This could then undergo a diastereoselec-
methodologies for the synthesis of this class of com- tive Pictet–Spengler cyclization[10–12] to provide the in-
pounds[6] led us to investigate an easy and useful doloquinolizidines 6 which are typically more difficult
asymmetric one-pot reaction sequence involving to prepare by other methods (Scheme 1).
simple and readily available starting materials. Asym-
metric cascade reactions have gained a lot of interest
in recent years because of the notable advantages as- Results and Discussion
sociated with them, including no need for time-con-
suming protection/deprotections steps or purification Our initial investigations were carried out with 1,3-cy-
of the intermediates.[7,8]
clohexanedione (1) and 2-hexenal (2c) in the presence
of catalytic amounts of TMS-protected prolinols 7a/
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quence by applying the same conditions for the
second step (Pictet–Spengler cyclization). Apart from
chloroform (entry 5), all other solvents afforded the
product with lower enantioselectivity (Table 1, en-
tries 2–4). Whereas no noticeable impact on the enan-
tioselectivity was observed, an increase in the rate of
the reaction was noted when changing the tempera-
ture from À208C to 08C (Table 1, entry 6). With
10 mol% of catalyst 7b, high enantioselectivity was
achieved when the reaction was performed at 08C in
dichloromethane (DCM) (Table 1, entry 10). The
product was isolated in 67% yield with 96% ee. The
yield and the enantioselectivity were slightly im-
proved when using 2 equivalents of acetic acid instead
of benzoic acid (Table 1, entry 11 vs. 10).
Scheme 1. Reaction of cyclic 1,3-diketone 1 with unsaturated
aldehydes 2 and tryptamine 4.
With the optimized conditions for the reaction of
1,3-cyclohexanedione (1) with 2-hexenal (2c) in hand,
we decided to explore the scope of this organocata-
7b. A series of optimization studies were conducted lyzed reaction by employing a wide range of aliphatic,
and the results are summarized in Table 1. The hemi- aromatic and heteroaromatic a,b-unsaturated alde-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
reaction was observed and only one diastereomer of selectivities for the methyl-, ethyl- and propyl-substi-
the desired product was formed. The product 6c was tuted derivatives were 93, 95 and 97%, respectively
isolated in 73% yield with 94% enantiomeric excess (Table 1, entries 1–3). The enantioselectivity further
(Table 1, entry 1). In an attempt to improve the enan- increased with increasing branching of the substituent
tioselectivity, other solvents were evaluated in the se- (i-Pr vs. n-Pr). In this case (R=i-Pr, Table 2, entry 4),
Table 1. Evaluation of solvents and catalysts in the Lewis Base-Brønsted acid catalyzed reaction sequence.[a]
Entry
Catalyst
Solvent
Temperature [8C]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b[e]
7b[e]
DCM
toluene
DCE
À20
À20
À20
À20
À20
0
0
0
0
0
73
–
–
–
–
62
71
75
74
67
79
94
92
89
87
94
94
94
96
94
96
97
CH3CN
CHCl3
DCM
DCM
DCM
toluene
DCM
DCM
7[d]
8[d]
9
10
11[d]
0
[a]
General conditions: 1) 0.2 mmol 1, 1.5 equiv. 2c, 20 mol% 7 in 1 mL solvent at the indicated temperature; 2) 0.4 mmol 4
and 0.4 mmol PhCO2H.
[b]
[c]
[d]
[e]
Yield after column chromatography.
Determined by chiral HPLC analysis.
Acetic acid was used.
10 mol% of catalyst was used.
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General and Efficient Organocatalytic Synthesis of Indoloquinolizidines
Table 2. Scope of different a,b-unsaturated aldehydes in the sequential reaction.[a]
Entry
Catalyst
Mol [%]
6
R
Yield[b] [%]
ee[c] [%]
1
2
3
4
7b
7b
7b
7b
7b
7b
7a
7a
7a
7a
7a
7a
10
10
10
10
10
10
20
20
20
20
20
20
6a
6b
6c
6d
6e
6f
6f
6g
6h
6i
Me
Et
n-Pr
i-Pr
n-heptyl
o-Br-C6H4
o-Br-C6H4
o-Cl-C6H4
p-Br-C6H4
p-(Me2N)-C6H4
p-MeO-C6H4
2-furyl
68
82
79
84
85
76
84
73
81
82
83
76
93
95
97
>99
95
92
98
96
90
90
86
85
5
6[d]
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
6j
6k
[a]
General conditions: 1) 0.2 mmol 1, 1.5 equiv. 2, catalyst 7 in 1 mL of DCM; 2) 0.4 mmol 4 and 0.4 mmol acetic acid in
1 mL of DCM.
[b]
[c]
[d]
Yield after column chromatography.
Determined by chiral HPLC analysis.
Product was isolated after the first step.
an excellent selectivity of >99% was achieved and However, increasing the reaction temperature from
the product was isolated in 84% yield. 08C to 108C improved the yields and shortened the
When using o-bromocinnamaldehyde under the op- reaction time without a substantial decrease in enan-
timized conditions, the product 6f was isolated in tioselectivity. Dimedone reacted with aliphatic substi-
76% yield with 92% ee (Table 2, entry 6). To our de- tuted aldehydes 2a–e in the same manner 1,3-cyclo-
light, we found that use of 20 mol% of catalyst 7a has hexanedione and provided the corresponding prod-
a beneficial effect on both rate and selectivity, the ucts 9a–e with good enantioselectivities (Table 3, en-
product being isolated in 84% yield with an improved tries 1–5). Aromatic aldehydes resulted in products
ee of 98% (Table 2, entry 7). Other substituted cin- with higher eeꢂs when using 20 mol% of less sterically
ACHTUNGTRENNUNGnamaldehydes were also employed and the products hindered catalyst 7a instead of 10 mol% of catalyst 7b
6g–j were isolated in good yields with high enantiose- (Table 3, entries 6 and 7).[13] Heteroaromatic substitut-
lectivities (Table 2, entries 8–11). However, in the ed aldehydes were also found to be good substrates
case of aromatic and heteroaromatic substituted alde- for the reaction (Table 3, entry 8).
hydes, purification of the products after the first step
The absolute configuration of the indoloquinolizi-
was crucial in order to obtain good yields for the final dines was determined by the X-ray analysis of 6f
products 6f–k. A simple filtration was enough to (Figure 1). The product has a 1,3-anti relationship be-
purify the compound for the second step. In general, tween the C-12b and C-14 protons and the configura-
electron-donating groups on the aromatic ring gave tion at these positions was assigned as S and R respec-
the products with slightly reduced enantioselectivities tively. The high diastereoselectivity occurring in the
(Table 2, entries 10 and 11). Using 2-furylacrolein as Pictet–Spengler cyclization is most likely due to steric
aldehyde gave the final key assembly in 76% yield repulsion taking place between the incoming indole
with 85% ee (Table 2, entry 12).
nucleophile and the axial proton of C-13.
To further enhance the applicability of this enantio-
Pyridoquinazolines and quinazolinones are impor-
selective organocatalyzed addition-cyclization reac- tant synthetic intermediates for the preparation of
tion, we tested another cyclic 1,3-dicarbonyl com- biologically active compounds. The generality of this
pound and our results are shown in Table 3. Dime- three-component reaction together with the impor-
done 8 proved to be an excellent substrate for this re- tance of nitrogen-containing heterocycles stimulated
action sequence and gave the desired products in high us to investigate other binucleophiles in the second
yields and excellent selectivities. Due to the low solu- part of this sequence. For this purpose, the hemiacetal
bility of dimedone in DCM at 08C, the reactions re- formed by the reaction of 1,3-cyclohexanedione (1)
quired longer times and yields were unsatisfactory. and 4-methylpentenal (2d) in the presence of 10
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Table 3. Scope of different a,b-unsaturated aldehydes in the reaction with dimedone and tryptamine.[a]
Entry
Catalyst
Mol [%]
9
R
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
7b
7b
7b
7b
10
10
10
10
10
20
20
20
9a
9b
9c
9d
9e
9f
9j
Me
Et
n-Pr
i-Pr
n-heptyl
o-Br-C6H4
p-MeO-C6H4
72
79
81
85
83
64
81
78
91
98
93
98
7b
94
[d]
7a[d]
7a[d]
7a[d]
94 (90)[e]
78 (76)[e]
90
9k
2-furyl
[a]
General conditions: 1) 0.2 mmol of dimedone, 1.5 equiv. 2, catalyst 7 in 1 mL of DCM; 2) 0.4 mmol 4 and 0.4 mmol acetic
acid in 1 mL of DCM.
Yield after column chromatography.
Determined by chiral HPLC analysis.
Product was isolated after the first step.
[b]
[c]
[d]
[e]
Number in brackets refers to the enantiomeric excess of the reaction conducted with 10 mol% of catalyst 7b.
formed during the reaction. In contrast to o-amino-
benzylamine 10, anthranilamide 13 reacted with the
aromatic nitrogen with the hemiacetal and the ring
was closed by the nitrogen of the amide group. The
product was isolated in 67% yield with an excellent ee
of 99% [Scheme 2 (c)]. These reactions not only pro-
vide the first enantioselective access to this class of
heterocycles but show that in principle all types of
amine containing bis-nucleophiles can be employed in
this reaction.
The regioselectivity and the configuration of the
cyclization product 14 were determined from the
single-crystal X-ray analysis (Figure 2). Unlike the
case of indoloquinalizidones, the protons at C-6a and
C-8 are on the same side showing that the product
arises from the thermodynamic control rather than
the kinetic control. Product 14 was thermodynamical-
Figure 1. Crystal structure of 6f.[14]
ly more stable because of the equatorial orientation
of the amide nitrogen.
mol% 7b was treated with o-aminobenzylamine 10
and 2 equivalents of acetic acid. The reaction pro- Conclusions
ceeded smoothly and the hemiacetal selectively react-
ed with the primary benzylamine moiety. Ring closure In summary, we have developed a new efficient and
via a diasteroselective aza-Mannich reaction provided general enantioselective multicomponent addition-
compound 11 in 76% yield with >99% ee [Scheme 2 cyclization sequence using simple and commercially
(a)]. Under the previously optimized conditions, the available starting materials such as cyclic 1,3-dicar-
same sequence has been applied to dimedone 8 to get bonyl compounds, unsaturated aldehydes and trypt-
the analogue 12 in 72% yield with 94% ee [Scheme 2
ACHTUNGTRENNUNG
(b)].
Using o-aminobenzamide 13 as nucleophile gave an volves the creation of four new bonds and two chiral
interesting pyridoquinazolinone 14 as product. We centers. A range of aliphatic, aromatic and heteroaro-
were pleased to find that only one regioisomer was matic aldehydes was tolerated in the cyclization,
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Adv. Synth. Catal. 2011, 353, 2853 – 2859

General and Efficient Organocatalytic Synthesis of Indoloquinolizidines
Scheme 2. Sequential reaction of 1,3-diketones, unsaturated aldehydes and aminobenzylamine (a), (b) or anthranilamide (c).
Experimental Section
General Experimental Procedure
In
a screw-cap tube were placed 26 mL (1.5 equiv.,
0.3 mmol) of crotonaldehyde 2a and 12 mg (0.1 equiv.,
0.02 mmol) of the catalyst 7b in 1.0 mL of dry DCM and the
contents were stirred at 08C for 10 min. 24 mg (1.0 equiv.,
0.2 mmol) of 1,3-cyclohexanedione 1 were added to the re-
action and stirring was continued until the complete disap-
pearance of the diketone. The reaction mixture was allowed
to warm to room temperature and diluted with 1 mL of
DCM. 64 mg (2 equiv., 0.4 mmol) of tryptamine and 20 mL
(2 equiv., 0.4 mmol) of acetic acid were added to the tube
and heated at 508C for overnight. The crude reaction mix-
ture was directly loaded for the column chromatography on
silica gel to get the product 6a; yield: 42 mg (0.14 mmol,
68%).
Figure 2. Crystal structure of 14.[14]
14-Methyl-3,4,6,7,12,12b,13,14-octahydroindolo-
[2’,3’:3,4]pyridoACTHNUTRGNE[UNG 1,2-a]quinolin-1(2H)-one (6a): IR (film):
yielding products in high yields with excellent enan-
tioselectivity. The high diastereoselectivity for the
Pictet-Spengler cyclization further increases the value
of this sequential reaction process. Furthermore, we
were for the first time able to extend this methodolo-
gy to amine containing bis-nucleophiles which al-
lowed fast access to valuable pyridoquinazolines and
quinazolinones in a highly enantioselective manner.
The method presented opens up a new perspective re-
garding the exploitation of sequential reactions to
synthesize various heterocycles as principally all kinds
of nitrogen containing bis-nucleophiles can be em-
ployed in this reaction sequence.
n=3826, 3188, 2963, 2925, 2867, 1578, 1524, 1441, 1359,
1302, 1251, 1184, 1109, 1036, 952, 819, 742 cmÀ1; H NMR
1
(600 MHz, CD2Cl2): d=1.09 (d, J=6.9 Hz, 3H), 1.65 (td, J=
12.7, 4.9 Hz, 1H), 1.80–1.90 (m, 1H), 1.93–1.98 (m, 1H),
2.22–2.27 (m, 2H), 2.30 (ddd, J=13.0, 4.1, 2.1 Hz, 1H), 2.48
À2.52 (m, 2H), 2.72 (ddd, J=5.3, 3.8, 1.9 Hz, 1H), 2.79
(dddd, J=14.4, 11.8, 4.7, 2.4 Hz, 1H), 3.09–3.03 (m, 1H),
3.17 (ddd, J=13.5, 12.0, 3.8 Hz, 1H), 4.16 (dd, J=13.6,
3.4 Hz, 1H), 4.66 (d, J=12.3 Hz, 1H), 6.98 (t, J=7.4 Hz,
1H), 7.04 (t, J=7.5 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.28
(d, J=8.1 Hz, 1H), 9.28 (s, 1H); 13C NMR (150.9 MHz,
CD2Cl2): d=20.37, 22.21, 22.29, 23.11, 27.38, 34.34, 35.87,
45.05, 50.12, 63.76, 107.99, 111.05, 111.42, 117.75, 119.17,
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121.43, 126.72, 134.40, 136.38, 159.09, 193.80; LC-MS (ESI):
m/z=307.25, calcd. for C20H23N2O: 307.41; [a]D: À50.9 (c
2.7, CHCl3, 93% ee); HPLC (AD-H column, n-hexane/2-
propanol=85/15, flow rate=1 mLminÀ1): major enantio-
mer: tR =9.97 min, minor enantiomer: tR =13.26 min.
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Acknowledgements
The authors would like to thank the DFG (SPP 1179) for fi-
nancial support and the Swiss National Science Foundation
(SNSF) for a stipendium given to C.M.R.V.
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Adv. Synth. Catal. 2011, 353, 2853 – 2859
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