Catalytic enantioselective aza-Henry reaction with broad substrate scope

Article abstract of DOI:10.1021/ja056594t

In situ generated azomethines from readily available precursors react with nitromethane in the presence of 120 mol % of CsOH·H₂O and 12 mol % of quinine- and cinchonidine-derived quaternary ammonium chlorides to provide the corresponding aza-He

Full text of DOI:10.1021/ja056594t

Published on Web 11/25/2005
Catalytic Enantioselective Aza-Henry Reaction with Broad Substrate Scope
Claudio Palomo,* Mikel Oiarbide, Antonio Laso, and Rosa L o´ pez
Departamento de Qu ´ı mica Org a´ nica I, Facultad de Qu ´ı mica, UniVersidad del Pa ´ı s Vasco, Apdo. 1072,
2
0080 San Sebasti a´ n, Spain
Received October 3, 2005; E-mail: qoppanic@sc.ehu.es
The reaction of nitrocompounds with azomethine functions to
Table 1. Screening of Bases and Quaternary Ammonium Salts in
the Reaction of R-Amido Sulfones 1a/2a with Nitromethane
a
afford 1,2-nitroamines, the aza-Henry (or nitro-Mannich) reaction,1
substrate
salt
base
product
conv. (%)b
ee (%)c
is a highly valuable C-C bond forming process. The resulting
2
3
nitroamine adducts can either be reduced, producing 1,2-diamines,
1
1a
a
5
5
5
5
5
5
6
6
7
7
Cs2CO3
CsOH‚H20
Cs2CO3
CsOH‚H20
K2CO3
KOH
3a
3a
4a
4a
3a
3a
3a
3a
33
>95
23
90
38
36
40
>95
17
82
90
65
65
80
82
76
85
44
84
4
or oxidized, affording R-amino acids. While the production of both
families of target molecules in nonracemic form bears considerable
interest, the use of the aza-Henry approach in that endeavor remains
nearly unexplored because of the long-standing lack of (catalytic)
asymmetric versions. Several groups have recently reported enan-
tioselective aza-Henry protocols involving metallic as well as
purely organic catalysts. Despite the remarkable levels of selectivity
so far reported,5 these methods are restricted, with almost no
2
2
1
1
1a
1a
1a
a
a
a
a
Cs CO3
2
5
CsOH‚H 0
2
6
Cs2CO3
ent-3a
ent-3a
1
a
CsOH‚H20
90
,6
7
exception, to non-enolizable aldehyde-derived azomethines. The
a
Reactions conducted at 0.5 mmol scale in 1.5 mL of toluene using a
availability of catalytic, enantioselective protocols also suitable for
enolizable substrates would considerably expand the aza-Henry
reaction. We have found recently that R-amido sulfones are
appropriate in situ precursors of enolizable aldehyde-derived
azomethine compounds in the context of the asymmetric Mannich
reaction. In connection to our recent interest in the area, we
present here a new asymmetric aza-Henry technology with broad
substrate scope based on the use of R-amido sulfone substrates9
and phase transfer catalysis (PTC).
nitromethane:base:ammonium salt molar equivalent ratio of 5:3:1.2 at -40
°
C for 40-44 h. b Determined by H NMR. Determined by HPLC.
1 c
In subsequent experiments, it was found that catalytic quantities
of 5 in combination with CsOH‚H
for the reaction of nitromethane with a variety of R-amido sulfones
. As data in Table 2 show, the enantiomeric excesses are generally
2
O (120-150 mol %) sufficed
8
5g
1
high for aryl-substituted R-amido sulfones (1h-m) irrespective of
the electronic nature of the aromatic ring: heteroaromatic azome-
thines being also tolerated (1n). Most remarkably, the aza-Henry
reaction with an array of enolizable aldehyde-deriVed azomethines
gaVe enantiomeric excesses regularly aboVe 94%. Hence, both
linear as well as branched chain alkyl R-amido sulfones 1a-g,
which show uneven degrees of steric hindrance, gave the corre-
sponding adduct 3 in good yields and enantiomeric excesses in the
94-98% range. Again, catalyst 5 performed slightly better than 6
(compare entries 1/2, 3/4, and 10/11).
Given that in situ generation of azomethines from R-amido
sulfones requires stoichiometric base,10 the base-promoted, nonse-
lective background aza-Henry reaction constitutes an initial ob-
stacle.11 It seemed that phase transfer conditions using chiral
quaternary ammonium salts12 in combination with a nonsoluble base
would render the competitive undesired reaction marginal.
The initial screen of several commercially available chiral
quaternary ammonium salts 5-7 and inorganic bases for the
reaction of R-amido sulfone 1a and nitromethane in toluene as
solvent was informative (eq 1 and Table 1). After 44 h of stirring
Additional observations gave further insights on the requirements
of and role played by the base and the catalyst. Thus, amine bases,
such as DBU, also gave good conversions but at the expense of
the enantioselectivity.15 The achiral amidinium nitronate, initially
generated in this instance upon nitromethane-base proton transfer,
may likely contribute to the racemic background process. On the
other hand, as results in eq 2 show, catalyst 5 alone is not capable
of promoting the reaction between 10 and nitromethane, and a
scenario with the cinchona catalysts acting as concurrent acid and
13
at -40 °C, only CsOH‚H
2
O
exhibited, among the bases tested,
nearly complete conversion; in all other cases, conversions remained
below 40%. As is often customary, while quinine derivative 5 and
cinchonidine derivative 6 provided products with R configuration,
cinchoninium salt 7 afforded the products with opposite configu-
ration.14 Good enantioselectivities were attained with all three salts
when N-Boc sulfone 1a was employed, but the reactions with the
corresponding Cbz sulfone 2a were less satisfactory.
base16 can be ruled out in this system. Clearly, CsOH‚H
2
O does
not merely act as the base for N-acyl imine formation but also
intervenes during the subsequent aza-Henry reaction. In addition,
the free hydroxyl group in catalysts 5-7 plays a key role in substrate
activation since the corresponding catalysts 8 and 9, whose alcohol
group has been protected in the form of benzyl ether, showed
17622
9
J. AM. CHEM. SOC. 2005, 127, 17622-17623
10.1021/ja056594t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Aza-Henry Reaction of Nitromethane and Nitroethane
with Azomethines Generated from R-Amido Sulfones 1 under
PTCa
Supporting Information Available: Complete experimental pro-
1
13
cedures, H and C spectra, HPLC chromatograms, and stereochemical
assignments. This material is available free of charge via the Internet
at http://pubs.acs.org.
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1-naphthyl
2-furyl
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4-MeOC6H4
4-ClC6H4
3
3
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82
79
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72
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72
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3
84
g
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91 (90:10)
94 (93:7)g
g
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90 (95:5)
98 (75:25)g
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8
972. (b) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol.
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Chem. 2004, 69, 7303-7308.
b
1
:CH3NO2:5:CsOH‚H2O in a 1:5:0.12:1.3 molar ratio. Isolated yields after
(10) Aromatic N-acyl imines can be obtained as isolable, relatively stable
compounds upon treatment with stoichiometric potassium carbonate.
See: (a) ref 6a,c. (b) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J.
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c
column chromatography. Determined by HPLC (see the SI for details).
The number in parentheses refers to the product after a single crystallization
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d
e
of syn/anti diastereomers in parentheses.
(
11) Ballini, R.; Petrini, M. Tetrahedron Lett. 1999, 40, 4449-4452.
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(
significantly lower efficiency (conversions typically <10%). This
(
c) Lygo, B.; Andrews, P. I. Acc. Chem. Res. 2004, 37, 518-525. (d)
17
result contrasts with previous observations and suggests that the
present catalysts exhibit dual functions;18 eventually, a hydrogen
bond may be formed between the hydroxyl group and the nitro
group’s oxygen, facilitating nitronate formation, and/or between
the hydroxyl and the azomethine’s nitrogen, activating the elec-
trophile and rigidifying transition structure.
The potential of this catalytic approach is further demonstrated
by the reaction of azomethine precursors 1a,h-j with nitroethane
to afford adducts 11a,h-j in syn:anti relationships up to 95:5 and
enantiomeric excesses in the range of 90-98% for the major syn
diastereomer. Finally, most products are crystalline, and essentially,
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1
(
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961-998.
15) For 3a: 48% ee in toluene (90% conv.); 18% ee in trifluoromethylbenzene
(
(
60% conv.). The selectivity could be improved up to 70% ee in a 1:1
mixture of toluene and dichloromethane.
(
16) (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9
906-9907. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.;
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27, 11256-11257 and references therein.
(17) O-alkylation of cinchone derivatives has proven to provide more efficient
catalysts for PTC: (a) ref 12. (b) ref 13. (c) Corey, E. J.; Noe, M. C.; Xu,
F. Tetrahedron Lett. 1998, 39, 5347-5350. (d) Corey, E. J.; Zhang, F.-
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enantiopure compounds can be obtained by direct crystallization
of the crude nitroamines.19
(
In conclusion, a catalytic, highly enantioselective aza-Henry
methodology is described, which works under PTC conditions. As
salient features, the new method involves readily available R-amido
sulfone substrates20 and commercial catalysts, making it easily
scalable. Most important, it is the first protocol amenable to
enolizable aldehyde-derived azomethine substrates, thus consider-
ably expanding the potential of the aza-Henry reaction in synthesis.
2
962. (c) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem.
Soc. 2004, 126, 6844-6845. (d) Ooi, T.; Ohara, D.; Fukumoto, K.;
Maruoka, K. Org. Lett. 2005, 7, 3195-3197.
19) For assignment of the configuration of adducts 3 and 11, see the Supporting
Information.
(
(20) For representative transformations eventually amenable for PTC, see the
following. Alkinyl-metal additions: (a) Mecozzi, T.; Petrini, M. J. Org.
Chem. 1999, 64, 8970-8972. Mannich reaction: (b) Nejman, M.;
Sliwi n´ ska, Zwierzak, A. Tetrahedron 2005, 61, 8536-8541. (c) Schunk,
S.; Enders, D. Org. Lett. 2001, 3, 3177-3180. (d) Enders, D.; Oberb o¨ rsch,
S. Synlett 2002 471-473. Strecker reaction: (e) Banphavichit, V.;
Chaleawlertumpon, S.; Bhanthummavin, Vilaivan, T. Synth. Commun.
Acknowledgment. This work was financially supported by The
University of the Basque Country (UPV/EHU), and Ministerio de
Educaci o´ n y Ciencia (MEC, Spain). A Ram o´ n y Cajal contract to
R.L. and a predoctoral grant to A.L., both from MEC, are
acknowledged.
2004, 34, 3147-3160.
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J. AM. CHEM. SOC.
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