Chiral phosphoric acid-catalyzed enantioselective three- component aza-diels-alder reactions of aminopyrroles and aminopyrazoles

Article abstract of DOI:10.1002/adsc.201400093

A highly stereoselective three-component Povarov reaction, catalyzed by (R)- and (S)-BINOL hydrogen phosphate, was achieved for the first time with aminopyrroles and aminopyrazoles as 2-azadiene precursors. A variety of aldehydes, enecarbamates, amino-substituted azines participated in the reaction to afford the tetrahydropyrrolopyridines and tetrahydropyrazolopyridines in good yields with excellent diatereo- and enantioselectivities. A stereochemical model is proposed to account for the observed absolute stereochemistry.

Full text of DOI:10.1002/adsc.201400093

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DOI: 10.1002/adsc.201400093
Chiral Phosphoric Acid-Catalyzed Enantioselective Three-
Component Aza-Diels–Alder Reactions of Aminopyrroles
and Aminopyrazoles
Julien Brioche,+a Thibaut Courant,+a Lilian Alcarez,b Mark Stocks,b Mark Furber,b
Jieping Zhu,c,* and Gꢀraldine Massona,*
a
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette Cedex, France
Fax : (+33)-1-6907-7247; e-mail: geraldine.masson@cnrs.fr (homepage: http://www.icsn.cnrs-gif.fr/spip.php?article225)
AstraZeneca R & D Mçlndal, SE-43183 Mçlndal, Sweden
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
b
c
Fꢀdꢀrale de Lausanne (EPFL), EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
Fax : (+41)-21-693-9740; e-mail: jieping.zhu@epfl.ch (homepage: http://lspn.epfl.ch)
+
Both authors contributed equally to this project.
Received: January 24, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400093.
Abstract: A highly stereoselective three-component
Povarov reaction, catalyzed by (R)- and (S)-BINOL
hydrogen phosphate, was achieved for the first time
with aminopyrroles and aminopyrazoles as 2-aza-
diene precursors. A variety of aldehydes, enecarba-
mates, amino-substituted azines participated in the
reaction to afford the tetrahydropyrrolopyridines
and tetrahydropyrazolopyridines in good yields
with excellent diatereo- and enantioselectivities. A
stereochemical model is proposed to account for
the observed absolute stereochemistry.
containing 2-azadiene cycloaddition partners, high-
lighting a need for development in this area.
We recently described the first examples of three-
component enantioselective Povarov reaction of alde-
hydes (2), anilines (3), and enecarbamates
4
(Scheme 1) leading to the rapid and efficient genera-
tion of a range of 4-amino-1,2,3,4-tetrahydroquino-
lines 1.[6a,d,f] As a continuation of this research pro-
gram, we wanted to extend this transformation to
amino-substituted aromatic substrates other than ani-
lines. In particular, we were interested in using amino-
pyrroles 6 and aminopyrazoles 7, as new partners of
Keywords: asymmetric synthesis; aza-Diels–Alder
reaction; chiral phosphoric acid; organocatalysis;
Povarov reaction
The chiral fused tethahydropyridines are found in
a large number of natural products as well as in many
biologically active compounds.[1] Therefore, the search
for new efficient and enantioselective methods for
their synthesis is an active field of interest.[2]
The Povarov reaction offers an efficient method for
the preparation of tetrahydroquinolines from simple
N-arylimines and electron-rich alkenes in an atom-
economic fashion.[3] Recently, much work has been
devoted to the enantioselective Povarov reaction with
a wide variety of dienophiles such as enol ethers,[4] cy-
clopentadienes,[4a,b,5] enamine derivatives,[6,7] vinylin-
doles[8] and styrenes.[9] Despite these great achieve-
Scheme 1. Catalytic enantioselective three-component Po-
ments, there are few reports of modifying the aniline- varov synthesis of fused tethahydropyridines.
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Julien Brioche et al.
Scheme 3. Optimized sequence for the three-component
synthesis of tetrahydropyrrolo[3,2-b]pyridine.
Scheme 2. Synthesis of 4-amino-2-cyanopyrrole 11.
AHCTUNGTRENNUNG
the three-component aza-Diels–Alder reactions. This the
would lead to the rapid and efficient generation of tetrahydropyrrolo
a new range of fused azaheterocyclic compounds such and diastereomer in 50% yield with 94% ee. The cis-
as tetrahydropyrrolo[3,2-b]pyridines and tetra- relative stereochemistry of 8a was assigned by
hydropyrazolo[4,3-b]pyridines 9 with potential and NOESY experiments and X-ray analysis of racemic
Povarov
reaction,
providing
the
AHCTUNGTRENN[GUN 3,2-b]pyridines 8a as a single regio-
A
8
ACHTUNGTRENNUNG
largely unexplored biological properties. However, product (see the Supporting Information) and the
the development of such a Povarov reaction is (2S,4S)-absolute configuration was assumed by analo-
quite challenging, as the aminoheterocycles readily gy with the cycloadducts obtained in our previous
undergo oxidative degradation and are difficult to works.[6a,d,f] Similarly, when the (S)-BINOL hydrogen
handle under acidic conditions due to their tendency phosphate-derived catalyst (S)-5 was employed, the
to isomerize into imine forms.[10] In this context, we antipode of 8a was formed with 94% ee.
planned to prepare such five-membered nitrogen het-
With the optimized mild reaction conditions in
erocycles from a simple nitration of the corresponding hand, the scope of this sequential process was studied.
heterocyles followed by reduction of the nitro group. As shown in Table 1, the reaction was applicable to
In addition, the incorporation of electron-withdrawing a wide range of electron-rich and electron-poor aro-
substituents on the heterocycle was expected to favor matic aldehydes to afford cis-2,4-disubtituted 7-
the enamine forms, hence improving their stability in aminotetrahydropyrrolo
ACHTUNGTRNE[NUNG 3,2-b]pyridine-2-carbonitrile
the presence of chiral phosphoric acid catalysts.[10c,11]
8 with both high diastereo- and enantioselectivities.
To validate this hypothesis, we carried out the nitra- The reactions involving aliphatic aldehydes tend to be
tion/reduction sequence starting from 2-cyanopyrrole considerably more capricious due to the competitive
10. Nitration of 10 with nitric acid under standard isomerization of the in situ formed aliphatic N-aryli-
conditions[12] followed by N-protection afforded the mine to the corresponding enamine.[6a,d,f] As observed
N-Boc derivative 6 in 44% overall yield (Scheme 2). in our previous works, lowering the reaction tempera-
Among various conditions reported for the reduction ture led to the expected cycloadduct 8e in a good
of the nitro group, we selected the mild catalytic hy- yield and excellent enantioselectivity (entry 4,
drogenation conditions that should allow an access to Table 1).
the pure product without requiring a purification pro-
We have then extended this sequential procedure
cess. The use of H2, Pd/C or Pd(OH)2 in AcOEt gave to nitropyrazoles 7 as partners of the three-compo-
a complete reduction of the nitro group but unfortu- nent Povarov reaction. In most of the cases, the cis-cy-
nately the corresponding 4-amino-2-cyano-1H-pyrrole cloadducts (9a–9h)[14a] were obtained in moderate to
11 was prone to degradation during its isolation. To good yields (over two steps) and with high enantiose-
overcome this, we envisaged to directly employ the lectivities. Aromatic (entries 5 to 9), a,b-unsaturated
crude hydrogenation product in the three-component (9g, entry 11) and aliphatic aldehydes (9h, entry 12)
Povarov reaction using our previously optimized con- can readily be used in the process. Surprisingly, the
ditions with benzaldehyde, N-benzylvinylcarbamate trans-isomers[14b] were formed exclusively when the 3-
and 10 mol% of (R)-5.[13] Unfortunately, the one-pot chlorobenzaldehyde (entry 13), 4-bromobenzaldehyde
sequence carried out either in EtOAc or DCM led to (entry 14)
and
4’-chlorobiphenyl-4-carbaldehyde
the formation of the imine product only. This result (entry 15) were used as partners. The stereochemical
seems to indicate that the residual palladium species relationship was confirmed by the cis-trans isomeriza-
after hydrogenation may disturb the chiral phosphoric tion of cis-9d upon treatment with NaH, affording
acid-catalyzed IEDADA reaction. To our delight, trans-9d without loss of stereochemical integrity
much better results were obtained in a stepwise pro- (Scheme 4 and the Supporting Information).[6h,15] The
cess (Scheme 3) when the palladium catalyst was fil- nature of the N-vinylcarbamate was also examined.
tered off and the crude product was directly used in The used carbamate protecting groups, such as tert-
2
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Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component
Table 1. Chiral phosphoric acid-catalyzed enantioselective synthesis of tetrahydropyrrolo
[3,2-b]pyridines
8
and
tetrahydropyrazoloACHTUNGTRENNUNG
[4,3-b]pyridines 9.[a]
Entry
1
8 or 9
Yield [%][b]
ee [%][c]
8b
51
95
2
3
8c
50
56
93
95
8d
4
5
8e
9a
70
90
92[e]
95
6
7
9b
9c
70
57
95
91
8
9
9d
9e
65
90
93
99
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Julien Brioche et al.
Table 1. (Continued)
Entry
8 or 9
Yield [%][b]
ee [%][c]
10
9f
93
94
11
12
9g
9h
90
80
97[e]
84[e]
13
14
9i[d]
66
81
96
95
9j[d]
15
16
9k[d]
65
90
9l
84
70
96[e]
17
9m
91[e]
[a]
General conditions: 4-nitro-2-cyano-1H-pyrrole 11 or 4-nitro-1H-pyrazoles 12 (0.25 mol, 1.0 equiv.), Pd/C (10 wt%), H2
(balloon, 1 atm), then filtration and evaporation; aldehydes 1 (0.3 mmol, 1.2 equiv.), and catalyst (R)-5 (10 mol%).
Isolated yields after chromatography.
[b]
[c]
[d]
[e]
Enantiomeric excesses were determined by chiral HPLC analysis.
The ratio of trans/cis-stereomers was determined to be higher than 95:5 by H NMR.
1
Reaction performed at À308C to room temperature.
butyloxycarbonyl (Boc) were found to participate in
the reaction with good yields and enantioselectivities.
Finally, (E)-enecarbamates with b-substituents react-
ed smoothly to afford the 5,6-trans-6,7-trans-trisubsti-
tuted tetrahydropyrazoloACTHNUTRGENUGN[4,3-b]pyridines 9l and 9m in
good yields and high diastereo- and enantiomeric ex-
cesses (entries 16 and 17).
Interestingly, hydrogenolysis of tetrahydropyrazolo-
AHCTUNGTRENNUNG
Scheme 4. Complete cis-trans isomerization of cis-9d.
4
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Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component
merized to the 2,4-trans one with NaH. With b-substi-
tuted enecarbamates, trans,trans-trisubstituted fused
tetrahydropyridines were obtained in excellent dia-
stereo- and enantioselectivities.
Experimental Section
Scheme 5. Synthesis
b]pyridines 12
of
7-aminotetrahydropyrazoloACTHNGUTRENNU[G 4,3-
General Procedure
A suspension of pyrrole 6 or pyrrazole 7 (0.25 mmol) and
Pd/C (10 wt%) in AcOEt (5.0 mL) was stirred vigorously
for 20–24 h under an H2 atmosphere (balloon, 1 atm). The
reaction mixture was then filtered through a short pad of
Celiteꢂ and the filtrate was evaporated to dryness under
vacuum. To the solution of so-obtained crude product in
DCM (2.5 mL), were added catalyst 5 (10 mol%) and alde-
hyde (0.3 mmol), successively. After being stirred at room
temperature for 30 min, the reaction mixture was cooled to
08C (or À308C) and enecarbamate 4 (0.375 mmol) was
added. Stirring was continued for additional 1–3 h. The
crude product was purified by flash chromatography (SiO2,
heptane/EtOAc) to afford the desired three-component
adduct.
(Scheme 5). The presence of an NH bond donor can
be an important element responsible for biological ac-
tivity.
A plausible stepwise mechanism[3c,16] for the forma-
tion of these novel heterocycle-fused tetrahydropyri-
dines 8 and 9 is depicted in Scheme 6. In analogy with
the previous proposal,[6a,d,f] the enecarbamate attacks
imine 13, formed in situ, via a transition state 15,
wherein the phosphoric acid formed H-bonds with
both imine and 4.[17] The Mannich addition of enecar-
bamate 4 would then occur from the Si face of the N-
heteroazadiene 14 to produce the iminium ion inter-
mediate 15, which would undergo intramolecular
Friedel–Crafts reaction to deliver the desired product
8 or 9. In a control experiment, we were able to trap
the intermediate 15 by ethanol leading to the acyclic
Mannich adduct (see the Supporting Information).[18]
In conclusion, a highly enantio- and diastereoselec-
Acknowledgements
Financial support from ICSN, CNRS and Astrazeneca is
gratefully acknowledged. J.B. thanks AZ for a post-doctoral
tive Povarov reaction was developed with new azine- fellowship and T.C. thanks MESR, University of Paris XI for
a doctoral fellowship.
derived heteroazadienes. Catalyzed by chiral phos-
phoric acids, reaction of aminopyrroles or aminopyra-
zoles, generated in situ from the corresponding nitro
heterocycles, with aldehydes and enecarbamates af-
forded fused tetrahydropyridines in good yields with
excellent diastereo- and enantioselectivities. We also
demonstrated that the 2,4-cis-stereomer can be iso-
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Chiral Phosphoric Acid-Catalyzed Enantioselective Three-
Component Aza-Diels–Alder Reactions of Aminopyrroles
and Aminopyrazoles
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Julien Brioche, Thibaut Courant, Lilian Alcarez,
Mark Stocks, Mark Furber, Jieping Zhu,*
Gꢀraldine Masson*
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