Enantioselective aza-Henry reactions assisted by ZnII and N-methylephedrine

Article abstract of DOI:10.1002/anie.200502674

(Chemical Equation Presented) Hooray aza-Henry! A combination of zinc triflate, an amine base, and (-)-N-methylephedrine (NME), which can be easily recovered and reused, leads to high enantioselectivities in the aza-Henry reaction of N-Boc-protected aldimines and nitromethane (see scheme; Boc = tert-butyloxycarbonyl).

Full text of DOI:10.1002/anie.200502674

Angewandte
Chemie
reaction,[1] is a highly valuable C C bond-forming process.
The resulting 1,2-nitroamine adducts can be transformed into
1,2-diamines[2] by reduction[3] as well as a-amino acids by a
Nef oxidation.[4] Whereas 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 largely unexplored because of the long-standing lack
of (catalytic) asymmetric versions.[1,5] In this context, Shiba-
saki and co-workers[6] described the use of binaphthoxide
(binol)-based heterobimetallic complexes of ytterbium and
aluminum as catalysts of the reaction of nitro compounds with
N-phosphinoyl imines derived from aromatic aldehydes,
while Jørgensen and co-workers[7] used copper bis(oxazoline)
complexes to catalyze the reaction of silyl nitronates with a-
imino esters. These methods usually require a high catalyst
loading (20 mol%), and the substrate scope is limited with
regards to one or both of the reaction partners.[8] Three
alternative organocatalytic aza-Henry reactions using
unmodified nitro compounds have also appeared.[9] Johnston
and co-workers[9a] reported a chiral bisamidine triflate salt
that induced diastereoselective addition of nitroethane to
several N-Boc-protected aryl imines (Boc = tert-butyloxycar-
bonyl), specifically those bearing electron-withdrawing
groups, while Takemoto and co-workers described[9b] moder-
ate enantioselectivities in reactions of nitromethane and
aromatic N-phosphinoyl imines induced by bifunctional
ureas. Most recently, Yoon and Jacobsen[9c] have documented
a thiourea-based catalytic aza-Henry reaction of aromatic N-
Boc imines leading to high enantioselectivities. Again,
organocatalytic methods featured some important restrictions
regarding the substrate scope and/or selectivity.
À
Aza-Henry Reaction
Some of us recently found[10] that cooperative activation[11]
of nitro compounds and aldehydes towards the Henry
reaction can be effected by combination of Zn(OTf)2
DOI: 10.1002/anie.200502674
(OTf = trifluoromethylsulfonate),
(À)-N-methylephedrine
Enantioselective Aza-Henry Reactions Assisted
(NME),[12] and a tertiary amine, all of which are available
from commercial sources. This finding oriented new research
towards establishing the validity of this activation model in
related reactions. Our specific new finding is that the same
system can effect highly enantioselective aza-Henry reactions
(Scheme 1) of nitromethane and N-Boc aryl imines, thus
providing a new entry to enantioenriched diamines and aryl
glycines.
by ZnII and N-Methylephedrine**
Claudio Palomo,* Mikel Oiarbide, Rajkumar Halder,
Antonio Laso, and Rosa López
The addition reaction of nitro compounds to azomethine
functions, known as the aza-Henry (or nitro-Mannich)
[*] Prof. Dr. C. Palomo, Prof. Dr. M. Oiarbide, R. Halder, A. Laso,
Dr. R. López
Departamento de Química Orgµnica I
Facultad de Química
Universidad del País Vasco
Apdo. 1072, 20080 San Sebastiµn (Spain)
Fax: (+34)943-015-270
Scheme 1. The aza-Henry reaction between imines 1–4 and nitrome-
thane. PG=protecting group, MS=molecular sieves.
E-mail: qoppanic@sc.ehu.es
[**] This work was financially supported by the University of the Basque
Country (UPV) and the Ministerio de Educación y Ciencia (MEC,
Spain). A Ramón y Cajal contract to R.L. from the MEC and
predoctoral grants to R.H. and A.L. from UPVand MEC, respectively,
are acknowledged.
Our initial aim was to identify the best-suited N-protect-
ing group in the imine component in terms of both reaction
conversion and enantioselection.[13] By using this activation
system, N-sulphonyl and N-phosphinoyl imines 1 and 2,
respectively, led to the corresponding b-nitroamines 5 and 6
with poor enantioselectivity, if at all (Table 1). Gratifyingly,
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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117

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Table 1: Effect of the imine substituent (protecting group, PG) on the
yield and enantioselectivity of the aza-Henry reaction.[a]
used in excess, may play a dual role as base and as chiral
inductor. Additionally, as supported by results from entries 8
and 9 (Table 2), the reaction selectivity is essentially inde-
pendent of the nature of the amine base employed.
A preliminary evaluation of the reaction scope was
carried out by using a series of N-Boc-protected aryl imines
that vary in electronic character (Table 3). Imines 4, which
Imine
Ar
PG
Product
Yield [%]
ee [%][b]
1
2
3
4a
Ph
Ph
Ph
Ph
CH3C6H4SO2
Ph2PO
Cbz
5
6
7
8a
>99[c]
>99[c]
82
30
0
82
94
Boc
80
[a] Reactions were conducted on a 1 mmol scale (1–4) in nitromethane
(2 mL) using imine/Zn(OTf)2/iPr2EtN/(À)-NME in a 1:1:1:1.5 molar
ratio at À208C, except that for imine 2 which was conducted at room
temperature. [b] Determined by HPLC. See Supporting Information for
details. [c] Reaction conversion.
Table 3: Aza-Henry reaction of N-Boc imines 4 with nitromethane.[a]
Imine 4
Ar
Yield
[%][b]
Product 8
ee [%][c]
a
b
c
C6H5
2-CH3C6H4
4-CH3C6H4
81
75
90
92
85
80
86
73
97
98
59
65
78
95
70
66
97
99
92 (94)
the N-Cbz-protected imine
3
(Cbz = carbobenzyloxy)
88[d]
afforded 7 with relatively much better ee values. The highest
enantioselectivity (94% ee) was obtained in the reaction with
N-Boc-protected imine 4a, which furnished the correspond-
ing protected b-nitroamine 8a in 80% yield. A set of
experiments in which the quantities of Zn(OTf)2, iPr2EtN,
and (À)-NME were varied for the reaction between nitro-
methane and imine 4a proved informative (Table 2). Impor-
86[e]
d
3-CH3OC6H4
90 (99)
88[d]
e
f
g
h
i
j
k
l
4-CH3OC6H4
4-ClC6H4
4-F3CC6H4
3-NO2C6H4
4-NO2C6H4
4-CH3O2CC6H4
1-Naphthyl
91
96[f] (98)
92 (94)
90 (92)
87
94
94 (98)
93
Table 2: The effect of the quantities of metal triflate, amine base, and
amino alcohol ligand on the reaction between N-Boc imine 1a and
nitromethane.[a]
2-Naphthyl
3,5-Cl2,4-MeOC6H2
m
87[e] (95)
[a] Reactions conducted on a 1 mmol scale in dry nitromethane (2 mL)
for 15–16 h at À208C using Zn(OTf)2 (30%), iPr2EtN (30%); (À)-NME
(45%), and 4 Š MS (100 mgmmolÀ1), unless otherwise noted. [b] Yield
of the isolated product after column chromatography. [c] Determined by
HPLC after removal of traces of (À)-NME by column chromatography
(see Supporting Information for details). The number in parentheses
refers to the ee value for the product after a single crystallization from
hexane/ethyl acetate. [d] Zn(OTf)2 (20%), iPr2EtN (20%), and (À)-NME
(30%). [e] Zn(OTf)2 (30%) and (À)-NME (75%). [f] In the absence of
4 Š MS, 84% ee was attained.
Entry
Zn(OTf)2
[%][b]
Base
Base
[%][b]
(À)-NME
ee
[%][b]
[%][c]
1
2
3
4
5
6
7
8
9
30
20
10
0
30
30
30
30
30
iPr2EtN
iPr2EtN
iPr2EtN
4–5–
4–5–
7–5–
9–0–
Et3N
Bu3N
30
20
10
0
45
30
15
94
92
87
[d]
0
97
95
30
30
45
45
92
94
[a] Reactions conducted on a 1 mmol scale in nitromethane (2 mL) for
15–16 h at À208C. Virtually complete conversion was observed in all
experiments, except for entry 5. [b] Percentage values refer to the mole
percentage (%mol) of the catalyst constituents with respect to the N-
Boc-protected imine. [c] Determined by HPLC. [d] Reaction conversion:
40%.
bear electron-rich, electron-neutral, or electron-poor aryl
substituents, were well tolerated to give N-Boc b-nitroamines
8 in generally good yields and with high levels of stereo-
control.[14] The standard reaction conditions involved nitro-
methane as solvent, but other solvent systems, such as
mixtures of nitromethane and dichloromethane or toluene
(1:1 v/v), can also be used. It was also observed that the
presence of traces of moisture or protic contaminants in the
reaction mixture were detrimental to the enantioselectivity.
In this regard, the addition of 4 Š molecular sieves was
beneficial and gave the highest enantioselectivity in the
present aza-Henry reaction. A practical aspect of the method
is that a single recrystallization of the crude nitroamine from
hexane and or mixtures of ethyl acetate and hexane can
provide products of increased enantiomeric purity.
The elaboration of thus-obtained aza-Henry products into
1,2-diamines and amino acids, respectively, could be per-
formed using known procedures. For example, reduction of
the nitro group in 8a led to the known monoprotected
diamine 9,[15] while Nef oxidation under the conditions
described by Mioskowski and co-workers[16] followed by
methylation afforded the N-Boc-protected (R)-phenylglycine
tantly, substoichiometric quantities of the three activating
reagents sufficed for full conversion of the starting imine into
adduct 8a, with yields of about 80% and generally high ee
values. For example, a percentage mole (mol%) ratio of
30:30:45 and 20:20:30 for the three activating components
gave selectivities of 94% ee and 92% ee, respectively
(Table 2, entries 1 and 2). Loadings of Zn(OTf)2 of
10 mol% or lower resulted in enantiomeric excesses below
90% (Table 2, entry 3). Interestingly, while (À)-NME alone
(entry 4) or a combination of Zn(OTf)2 and (À)-NME in a
ratio of 30:45 (Table 2, entry 5) led to racemic product,
combinations of Zn(OTf)2 and (À)-NME in a ratio of 30:75 or
higher (entries 6 and 7) led to high enantioselectivities again.
These results demonstrate that the presence of a base is key
for success and suggest that the amino alcohol ligand, when
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Chemie
methyl ester 12 without apparent loss of optical integrity
(Scheme 2).[17] Further acetylation of 9 to the known com-
pound 10 allowed the absolute configuration of the adducts to
be confirmed.
[1] For recent advances on this reaction, see: B. Westermann,
Angew. Chem. 2003, 115, 161 – 163; Angew. Chem. Int. Ed. 2003,
42, 151 – 153.
[2] For a review on 1,2-diamines, see: D. Lucet, T. Le Gall, C.
Mioskowski, Angew. Chem. 1998, 110, 2724 – 2772; Angew.
Chem. Int. Ed. 1998, 37, 2580 – 2627.
[3] See, for instance: P. H. OꢀBrien, D. R. Sliskovic, C. J. Blankley,
B. Roth, M. W. Wilson, K. L. Hamelehle, B. R. Krause, R. L.
Stanfield, J. Med. Chem. 1994, 37, 1810 – 1822.
[4] For reviews, see: a) H. W. Pinnick, Org. React. 1990, 38, 655 –
792; b) R. Ballini, M. Petrini, Tetrahedron 2004, 60, 1017 – 1047.
For the application of this approach to the synthesis of optically
active a-amino acids; see: c) E. Foresti, G. Palmieri, M. Petrini,
R. Profeta, Org. Biomol. Chem. 2003, 1, 4275 – 4281.
[5] For non-asymmetric aza-Henry reactions, see: a) J. C. Anderson,
A. J. Blake, G. P. Howell, C. W. Ilson, J. Org. Chem. 2005, 70,
549 – 555; b) L. Bernardi, B. F. Bonini, E. Capitó, G. Dessole, M.
Comes-Franchini, M. Fochi, A. Ricci, J. Org. Chem. 2004, 69,
8168 – 8171.
Scheme 2. Assignment of the configuration of the adducts by trans-
formation into 1,2-diamines. DMSO=dimethyl sulfoxide.
[6] a) K. Yamada, S. J. Harwood, H. Gröger, M. Shibasaki, Angew.
Chem. 1999, 111, 3713 – 3715; Angew. Chem. Int. Ed. 1999, 38,
3504 – 3506; b) K. Yamada, G. Moll, M. Shibasaki, Synlett 2001,
980 – 982.
[7] a) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf,
K. A. Jørgensen, J. Am. Chem. Soc. 2001, 123, 5843 – 5844. For
latter versions using unmodified nitro compounds, see: b) N.
Nishiwaki, K. R. Knudsen, K. V. Gothelf, K. A. Jørgensen,
Angew. Chem. 2001, 113, 3080 – 3083; Angew. Chem. Int. Ed.
2001, 40, 2992 – 2995; c) K. R. Knudsen, K. A. Jørgensen, Org.
Biomol. Chem. 2005, 3, 1362 – 1364.
[8] The aza-Henry reaction with N-p-methoxyphenyl imines using
preformed nitropropane silyl nitronate in the presence of a CuII/
tBOX catalyst with generally good diastereo- and enantioselec-
tivities has been recently published, see: J. C. Anderson, G. P.
Howell, R. M. Lawrence, C. S. Wilson, J. Org. Chem. 2005, 70,
5665 – 5670.
[9] a) B. M. Nugent, R. A. Poder, J. N. Johnston, J. Am. Chem. Soc.
2004, 126, 3418 – 3419; b) T. Okino, S. Nakamura, T. Furukawa,
Y. Takemoto, Org. Lett. 2004, 6, 625 – 627; c) T. P. Yoon, E. N.
Jacobsen, Angew. Chem. 2005, 117, 470 – 472; Angew. Chem. Int.
Ed. 2005, 44, 466 – 468.
[10] C. Palomo, M. Oiarbide, A. Laso, Angew. Chem. 2005, 117,
3949 – 3952; Angew. Chem. Int. Ed. 2005, 44, 3881 – 3884.
[11] For recent reviews on cooperative activation of nucleophiles (or
pronucleophiles) and electrophiles, see: a) J.-A. Ma, D. Cahard,
Angew. Chem. 2004, 116, 4666 – 4683; Angew. Chem. Int. Ed.
2004, 43, 4566 – 4583; b) S. Kanemasa, K. Ito, Eur. J. Org. Chem.
2004, 4741 – 4753.
[12] For other recent uses of N-methylephedrine, such as the addition
of acetylides to aldehydes, see: a) N. K. Anand, E. M. Carreira, J.
Am. Chem. Soc. 2001, 123, 9687 – 9688; b) D. E. Frautz, R.
Fässler, E. M. Carreira, J. Am. Chem. Soc. 2000, 122, 1806 – 1807;
for imino-Reformatsky reaction, see: c) P. G. Cozzi, E. Rivalta,
Angew. Chem. 2005, 117, 3666 – 3669; Angew. Chem. Int. Ed.
2005, 44, 3600 – 3603.
[13] Benzaldehyde-derived imines from p-anisidine and benzylamine
did not react under the conditions described. These kind of
imines have been shown to be active against preformed silyl
nitronates in the presence of a Lewis acid. See, for instance,
reference [8].
[14] Apparently, heteroaromatic N-Boc-protected imines are less-
suitable substrates for the reaction. For instance, the aza-Henry
adduct from the furfuraldehyde N-Boc imine derivative was
obtained in 96% yield and with 66% ee.
In conclusion, the pool of available methods for the
asymmetric aza-Henry (nitro-Mannich) reaction has been
enhanced by the approach described here which features
a) tolerance to imines that bear aryl groups of diverse
electronic nature and substitution patterns, b) exclusive use
of commercially available reagents, in particular the relatively
low-cost N-methylephedrine as the recyclable chiral inductor,
and c) flexibility on the effective loading of the triggering
system, which varies from stoichiometric to about 10 mol%
with respect to the transformed imine substrate.
Experimental Section
In a typical procedure, diisopropylethylamine (1.05 mL, 6 mmol) was
added dropwise to a solution of anhydrous zinc triflate (2.18 g,
6 mmol) in nitromethane (40 mL) under a nitrogen atmosphere and
the resulting mixture was stirred at 258C for 1 h. The mixture became
yellow. After addition of (À)-(1R,2S)-N-methylephedrine (1.6 g,
9 mmol) and 4 Š molecular sieves (2.0 g), the resulting mixture was
stirred for an additional 2 h at the same temperature. The reaction
mixture was then kept for 10 min at À208C, imine 4a (4.1 g, 20 mmol)
was added, and the mixture was stirred for 21 h at À208C. The
reaction was quenched with 0.1m HCl (50 mL), and the mixture was
extracted with dichloromethane (3 ” 50 mL). The organic layer was
dried over MgSO4 and concentrated under reduced pressure.
Purification of the crude product by flash column chromatography
(ethyl acetate/hexane) afforded 8a (4.3 g, 80% yield). From the late
fractions of the column, 0.432 g of (1S,2R)-N-methylephedrine was
recovered. Recovery of the chiral ligand that remained in the acidic
aqueous phase was carried out by dropwise addition of a solution of
NaOH (20% w/v) until pH 10. The mixture was extracted with
CH2Cl2 (3 ” 10 mL), the organic layer was dried over MgSO4, and the
solvent was evaporated to afford an additional 1.12 g of (À)-NME
(1.55 g (97%) combined yield of chemically and optically pure (À)-
NME ligand).
Received: July 29, 2005
Published online: November 17, 2005
Keywords: amines · asymmetric catalysis · enantioselectivity ·
.
nitro compounds
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Communications
[15] P. H. OꢀBrien, D. R. Sliskovic, C. J. Blankley, B. Roth, M. W.
Wilson, K. L. Hamelehle, B. R. Krause, R. L. Stanfield, J. Med.
Chem. 1994, 37, 1810 – 1822.
[16] a) C. Matt, A. Wagner, C. Mioskowski, J. Org. Chem. 1997, 62,
234 – 235. For the application of this method to the synthesis of
a-hydroxy acids from b-nitro alcohols, see: b) B. M. Trost,
V. S. C. Yeh, Angew. Chem. 2002, 114, 889 – 891; Angew. Chem.
Int. Ed. 2002, 41, 861 – 863.
[17] Subjecting 8a (97% ee) to the conditions reported in referen-
ce [4c] (KMnO4, KOH, Na2HPO4) led to partially racemized 11a
(65% yield, 70% ee).
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