Tandem Chiral Cu(II) Phosphate-Catalyzed Deoxygenation of Nitrones/Enantioselective Povarov Reaction with Enecarbamates

Article abstract of DOI:10.1002/ejoc.201900547

A new catalytic enantioselective tandem deoxygenation/aza-Diels-Alder reaction of nitrones with enecarbamates was serendipitously discovered in the presence of chiral copper(II) diphosphate complexes. This process affords a wide range of 4-aminotetrahydroquinolines in respectable yields under mild conditions with good to excellent ee values.

Full text of DOI:10.1002/ejoc.201900547

A Journal of
Accepted Article
Title: Tandem Chiral Cu(II) Phosphate-Catalyzed Deoxygenation of
Nitrones/ Enantioselective Povarov Reaction with Encarbamates
Authors: Coralie Gelis, Guillaume Levitre, Vincent Guerineau, David
Touboul, Luc Neuville, and Géraldine Masson
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900547
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10.1002/ejoc.201900547
European Journal of Organic Chemistry
COMMUNICATION
Tandem Chiral Cu(II) Phosphate-Catalyzed Deoxygenation of
Nitrones/ Enantioselective Povarov Reaction with Encarbamates
Coralie Gelis, Guillaume Levitre, Vincent Guérineau, David Touboul, Luc Neuville, and Géraldine
*
Masson
Abstract: A new catalytic enantioselective tandem deoxygenation /
aza-Diels-Alder reaction of nitrones with enecarbamates was
serendipitously discovered in the presence of chiral copper(II)
diphosphate complexes. This process affords a wide range of 4-
aminotetrahydroquinolines in respectable yields under mild conditions
with good to excellent ee values.
corresponding metal salts[7b,8] could promote enantioselective
(3+2) cycloaddition to deliver valuable isoxazolidines 4. Indeed,
as the nitrones and enecarbamates can be activated by these
catalysts via hydrogen bonding[3b] and/or metal chelation,
reactivity and high stereoselectivity might be achieved (Scheme
1). However, our first attempts with chiral phosphoric acids were
totally unsuccessful, the starting materials being mainly recovered.
Therefore, we turned our attention to their corresponding more
active phosphate metal salts as viable catalysts for this
cycloaddition. Alkali or alkaline earth metal-phosphoric acid
complexes were not more effective as catalysts.[7b] But to our
surprise, when copper(II) phosphate salt CuII[3a]2 was used, the
reaction took a completely different course.[9] No isoxazolidine 4
was observed but instead a 4-amino-tetrahydroquinoleine 5a was
isolated in low yield albeit with excellent diastereo- and
enantioselectivity (Scheme 2). To explain this, we reasoned that
product arose from two events, namely a copper promoted
deoxygenation[10] and a copper phosphate catalyzed inverse
electron demand aza-Diels-Alder (IEDADA) reaction (also called
Povarov reaction)[6c,g,i-k, 11, 12] to give a 1,2,3,4-tetrahydroquinoline.
Introduction
Nitones are valuable and versatile building blocks in organic
synthesis because of their ready accessibility and high reactivity
in various transformations.[1] While a large amount of work has
been dealing with rearrangements, nucleophilic or radical
additions and CH functionalization among others,[1c] nitrones are
probably best known for their cycloaddition reactivity.[1d] In
particular, 1,3-dipolar cycloaddition reaction of nitrones with
various dipolarophiles, has been extensively investigated
especially in its catalytic asymmetric version.[2,3] Surprisingly,
enamides and enecarbamates, which commonly served as
dienophiles in cycloadditions,[4] have been rarely used as
dipolarophiles in the inverse electron demand (3+2)
cycloaddition.[2b,5] To the best of our knowledge, no catalytic
enantioselective version has been reported yet.
Scheme 2. Copper phosphate catalyzed deoxygenation and enantioselective
Povarov reaction.
Scheme 1. Catalytic enantioselective (3+2) cycloaddition synthesis of
trisubstituted isoxazolidines.
Results and Discussion
Being interested in this unexpected[13] enantioselective tandem
deoxygenation/Povarov reaction, we decided to optimize the
reaction conditions, with the aim of increasing the yield to a
synthetically-useful level while maintaining the high levels of
stereocontrol. The catalytic asymmetric methods do not require
isolation and prior purification of copper complex; catalyst freshly
prepared, can be utilized directly (entry 1, Table 1). Initial
experiments showed that the catalysts formation is sensitive to a
number of parameters. Presence of water during the copper(II)
phosphate complex preparation was crucial for obtaining the 4-
amino-tetrahydroquinoline 5a. As such, starting materials were
essentially recovered when the reaction was performed in dry
solvents or in the presence in molecular sieves from Cu(OMe)2
(entry 2 and 3).
In continuation of our research program in catalytic asymmetric
cycloadditions with enecarbamates,[6] we became interested in
exploring their reactivity in connection with nitrones. We
speculated that chiral phosphoric acid catalysts[7] or their
[a]
Dr. C. Gelis, Mr. G. Levitre, Mr V. Guérineau, Dr D. Touboul, Dr. L.
Neuville, Dr. G. Masson
Institut de Chimie des Substances Naturelles CNRS UPR 2301,
Université Paris-Sud, Université Paris-Saclay, 1, av. de la Terrasse,
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?article848
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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On the contrary, Cu(OH)2, probably also generated upon water
hydrolysis of Cu(OMe)2, proved to be a suitable precursor for
effective copper phosphate complex formation in the absence of
H2O.[14] Indeed, when the complex was prepared from Cu(OH)2 in
the absence of H2O in dry DCM/MeOH, the desired product was
formed (entry 4). However, the yield was further improved by
adding 0.5 eq of water as a protic additive (entry 5).[15] Then, other
copper salts were screened and showed lower activity compare
to Cu(OH)2 (entry 6 and 7). The yield increased from 38% to 56%
when 3 equiv. of nitrone 1a was used as the partner of
enecarbamate 2a (entry 8). Next, we studied the reactivity in
different solvents, and no improvement was observed when
toluene, or CHCl3 were used (entry 9 and 10).
Table 1. Synthesis of 4-aminotetrahydroquinoline:
conditions.[a]
a survey of reaction
Table 2. Scope of the organocatalytic enantioselective (3+2) cyclization.[a]
Yield
[%][b]
ee
[%][c]
Entry
CuLn
Ar
Additive
Solvent
1
2
Cu(OMe)2 4-ClC6H4 (3a)
Cu(OMe)2 4-ClC6H4 (3a)
Cu(OMe)2 4-ClC6H4 (3a)
Cu(OH)2 4-ClC6H4 (3a)
Cu(OH)2 4-ClC6H4 (3a)
-
DCM
DCM[d]
DCM[d]
DCM[d]
DCM
31
5%
0
97
-
3 Å MS
-
3
-
4
-
28
38
17
28
56
57
54
59
48
39
59
49
94
92
61
93
96
96
91
98
95
96
98
98
5
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
H2O[e]
6
CuCl2
CuO
4-ClC6H4 (3a)
4-ClC6H4 (3a)
DCM
7
DCM
8[f]
9[f]
Cu(OH)2 4-ClC6H4 (3a)
Cu(OH)2 4-ClC6H4 (3a)
DCM
Toluene
CHCl3
DCM
10[f] Cu(OH)2 4-ClC6H4 (3a)
11[f] Cu(OH)2
12[f] Cu(OH)2
13[f] Cu(OH)2
14[f] Cu(OH)2
15[f] Cu(OH)2
C6H5 (3b)
C6H5 (7a)
DCM
2,4,6-
(iPr)3C6H5
(7b)
DCM
C6H5 (3b)[g]
DCM
C6H5 (3b)[h]
DCM
[a] General conditions: CuLn (0.01 mmol), 3 (0.02 mmol) in DCM/MeOH (1/1, 2
mL), RT, 1.5 h and evaporation followed by addition of 1 (0.2 mmol), 2a (0.1
mmol) in DCM (2 mL), RT, 1 h. [b] Yields refer to chromatographically pure
products. The d.r. were determined by 1H NMR analysis to be higher than 98:2
in all cases. [c] Enantiomeric excess was determined by HPLC on a chiral
stationary phase: see the Supporting Information for details. [d] Freshly distilled
DCM. [e] With 0.5 equiv of H2O. [f] With 0.3 equiv of 1a. [g] CuII[3b]2 prepared
in 10 min. [h] 1 mmol scale relative to 2a.
[a] General conditions: Cu(OH)2 (0.01 mmol), 3b (0.02 mmol) in DCM/MeOH
(1/1, 2 mL), RT, 10 min and evaporation followed by addition of 1 (0.3 mmol), 3
(0.1 mmol) in DCM (2 mL), RT, 1 h. [b] Yields refer to chromatographically pure
products. The d.r. were determined by 1H NMR analysis to be higher than 98:2
in all cases. [c] Enantiomeric excess was determined by HPLC on a chiral
stationary phase.
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Phosphate screening revealed that the 3,3'-substituent on the
BINOL scaffold had a little effect on enantioselectivity, but did
impact the chemical yield (entry 8 vs 11-13). Indeed, the catalyst
bearing less-hindered 3,3'-substituents on the octahydrogenated-
BINOL such as phenyl group gave best result (entry 11). The
same effect was observed when BINOL 7a and 7b were used as
a ligand (entry 11 vs 12). However, these phosphates led to lower
yield and enantioselectivity than 3a and 3b (entry 10-13).
Although the yield remained moderate, we deemed it respectable
in light of this complex tandem process. The reaction time for the
Cu(II) complex formation could be reduced to 10 min without
affecting the overall process (entry 14). Finally, the reaction was
scaled up without affecting enantioselectivity, even if isolated
yield were somewhat reduced (entry 15).
With the optimal reaction conditions established (Table 1, entry
14), we next investigated the substrate scope of the reaction by
employing a variety of N-aryl nitrones 1. The reaction proceeded
well with decent yields and enantioselectivity in almost all cases
when nitrones derived from electron poor or electron rich aromatic
aldehydes were employed (5b to 5e). However, the reaction gave
a lower yield in the case of nitrone substituted at the ortho-position
5e, possibly due to steric effects. Remarkably, nitrones derived
from heteroaldehydes such as thiophene-3-aldehyde and 3-
furaldehyde were successfully engaged in this tandem
deoxygenation/Povarov process. Next, the N-substituent effect of
1 was also examined and it was found that its electronic property
had little yield effect. For instance, nitrones bearing both electron-
withdrawing (5h) and weak electron-donating (5i) substituents
afforded the desired products in better yield than strong electron-
donating (5j) substituent such as MeO group. An array of β-
substituted enecarbamates 2 including linear and branched ones,
were tested, resulting in the formation of the expected 4-amino-
Cu(OH)2 hence indicating the crucial role of phosphates ligands
on the deoxygenation step of nitrones. To clarify which species
participates in the deoxygenation of product, the reaction of
nitrone 1a with Cu(II)-phosphate CuII[3b]2 was performed in DCM
at RT. After 1h, nitrone 1a totally disappeared, reveling the
presence of N-arylimine 6a, benzaldehyde, nitroso compound 9a
and azobenzene 10a in the following 1/1.7/0.7/0.35 ratio,
respectively (eq 1). Partial hydrolysis of the nitrone 6a would
account for the presence of aldehyde. By that, N-
arylhydroxylamine could be released and subsequent oxidation
by Cu(II) would to furnish 9a. The resulting Cu(I) complex produce
during this last event is next suitable in promoting the
deoxygenation of nitrone to imine.[16,17] Possible implication of N-
arylhydroxylamine 11 was established by control experiment
showed in eq 2. Indeed, when one equivalent of N-
arylhydroxylamine was added to the reaction mixture, the number
of nitrone equivalent could be reduced in this cycloaddition
keeping overall yield constant. Moreover, when N-arylimine 6a
was used as the reactant in place of nitrone 1a, under otherwise
identical
conditions,
the
same
desired
enantiomer
tetrahydroquinolines 5a was obtained (eq 3).[18] Omitting copper
and performing the reaction with phosphoric acid 3b furnished the
cycloadduct 5a in similar yield and ee albeit with longer reaction
times (eq 4, 5 h vs. 1 h).[19] This indicated that the chiral copper(II)
phosphate complex might be the active catalyst in the
cycloaddition process. Nevertheless, at the present stage of the
development, we cannot exclude the possibility that phosphoric
acid is involved in catalytic cycle.
On the basis of the results obtained above and the previous
literature,[15]Erreur ! Signet non défini. a plausible mechanism is proposed
in Scheme 4. In the initial step, Cu(II) is probably reduced by the
N-arylhydroxylamine generated, during a partial hydrolysis of 1 to
tetrahydroquinolines (5k to 5m) with excellent enantioselectivities. form Cu(I) complex. This latter is able to reductively deoxygenate
It is also noteworthy that the silyl ether group was untouched in
this process. N-Fmoc carbamate and benzylthiocarbamate were
tolerated giving rise to the final cycloadducts 5n and 5o,
respectively, with slightly lower yields.
the nitrone 2 to the corresponding N-arylimine 6 and gives the
catalytically active Cu(II) phosphate complex.[10] While its exact
structure awaits further study, the MS spectra of complex show a
peak at m/z 1214.93 which indicates the formation of copper
bis(phosphate) complex.[20] Then, CuII[3b]2 could simultaneously
activate both N-arylimine 9 and enecarbamate 2 via metal ion
coordination and hydrogen bonding. Finally, an enantioselective
Mannich reaction would occur to form a transient imine 13, which
would further undergo an intramolecular Friedel–Crafts reaction
to deliver the (2S,3R,4S)-4-aminotetrahydroquinoline 5.[6i-k,11]
Scheme 3. Control experiments.
In order to gain some mechanistic insight, control experiments
were carried out (Scheme 3). No reaction took place with only
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Scheme 4. Assumed mechanism for the enantioselective tandem
deoxygenation/Povarov reaction.
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In conclusion, we have developed a highly efficient asymmetric
synthesis of chiral 4-aminotetrahydroquinolines through the
copper(II)/phosphate-catalyzed tandem deoxygenation/Povarov
reaction of nitrones with enecarbamates. This process allows the
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synthesis
of
various
tetrasubstituted
4-amino-
tetrahydroquinolines bearing 3 contigous stereocenters with
excellent diastereo and enantioselectivities. Further investigation
of the mechanistic insights is currently underway in our laboratory.
Experimental Section
Typical procedure for the synthesis of compound 5: In a flame dried
schlenk under argon were added copper(II) hydroxide (0.01 mmol),
phosphoric acid 3b (0.02 mmol) and degassed solvents (dichlormethane
1mL and methanol 1 mL). The mixture was stirred at room temperature for
10 minutes and concentrated under vacuum. After introduction of 2 mL of
degassed dichloromethane, Nitrone 1 (0.3 mmol) and enecarbamate 2
(0.1 mmol) were added and the reaction was stirred at room temperature
until complete consumption of starting materials. Reaction was
concentrated under reduced pressure to give a residue which was purified
by flash chromatography (SiO2, eluent: Petroleum ether: Ethyl Acetate) to
afford the desired product.
[7]
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Acknowledgments ((optional))
We thank ICSN and CNRS for financial support; C.G. and G.L.
thank Saclay University for the doctoral fellowships;
[8]
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Keywords: Copper phosphate • deoxygenation • aza-Diels-
Alder reaction • enecarbamate • heterocycle
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[18]
Absolute configuration determined by comparison of the specific rotation
and HPLC peak intensities with our previous work reported, see ref 5k.
We thank one referee for suggesting and highlighting this point.
Cu(I) complex was seen in MS (MALDI-TOF), but matrice could be
responsible for reduction (See supporting information).
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[19]
[20]
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10.1002/ejoc.201900547
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Cut and joint together: Chiral Copper
Tandem catalysis*
phosphate
promoted
complexes
tandem sequence of
efficiently
Coralie Gelis, Guillaume Levitre, Vincent
Guérineau, David Touboul, Luc Neuville,
Geraldine Masson*
a
deoxygenation/ [4+2] cycloaddition
reactions. This process gives access to
various tetrahydroquinolines with three
consecutive stereogenic centers in
good yields with excellent diastereo-
and enantioselectivity.
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Tandem Chiral Cu(II) Phosphate-
Catalyzed Deoxygenation of Nitrones/
Enantioselective Povarov Reaction
with Encarbamates
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