Phase-transfer-catalyzed asymmetric aza-Henry reaction using N-carbamoyl imines generated in situ from α-amido sulfones

Article abstract of DOI:10.1002/anie.200502646

(Chemical Equation Presented) A general approach to the catalytic asymmetric aza-Henry reaction has been developed. The combination of a commercially available phase-transfer catalyst (PTC) with a base is able to promote the in situ formation of N-carbamo

Full text of DOI:10.1002/anie.200502646

Angewandte
Chemie
Asymmetric Synthesis
DOI: 10.1002/anie.200502646
Phase-Transfer-Catalyzed Asymmetric Aza-
Henry Reaction Using N-Carbamoyl Imines
Generated In Situ from a-Amido Sulfones**
Francesco Fini, Valentina Sgarzani, Daniel Pettersen,
Raquel P. Herrera,* Luca Bernardi,* and Alfredo Ricci
Nucleophilic addition to the C=N bond of imine derivatives is
of paramount importance in organic chemistry for the
synthesis of functionalized amines and related nitrogen-
[
1]
containing compounds. In this transformation, the substitu-
ent on the nitrogen atom of the imine often plays a crucial
[
2]
role, thus strongly affecting the electrophilicity. In principle,
as well as guaranteeing sufficient reactivity, this N-substituent
should be easily removable after the reaction has taken place.
Both requirements are fulfilled by carbamoyl groups, such as
[
3]
tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
However, because of their inherent high reactivity, N-
carbamoyl imines are rather sensitive to moisture, their
purification (though often not necessary) is rather trouble-
some, and their storage requires some precautions. Further-
more, the isolation of N-carbamoyl imines derived from
aliphatic enolizable aldehydes has not been reported, as they
[
4]
readily tautomerize to the corresponding ene carbamate,
thus resulting in a considerable limitation to the generality of
their applications. A possible way to overcome these draw-
backs is the in situ generation of the imine through the use of
carbamates with a good leaving group at the carbon atom a to
the nitrogen atom. Among the suitable imine precursors
available, a-amido sulfones 1 are particularly attractive as
they are bench-stable solids and can be very easily obtained
by the condensation of a carbamate and a sodium aryl
[
5]
sulfinate with the appropriate aldehyde. As a-amido
[
+]
[*] Dr. R. P. Herrera
Departamento de Química Orgµnica
Universidad de Alicante
Apdo 99, 03080 Alicante (Spain)
Fax: (+39)051-209-3654
E-mail: rph@alu.ua.es
F. Fini, V. Sgarzani, Dr. D. Pettersen, Dr. L. Bernardi, Prof. A. Ricci
Dipartimento di Chimica Organica “A. Mangini”
Università di Bologna
Viale Risorgimento 4, 40136, Bologna (Italy)
Fax: (+39)051-209-3654
E-mail: nacca@ms.fci.unibo.it
+
[
] Current address: Dipartimento di Chimica Organica “A. Mangini”
Università di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
[
**] We acknowledge financial support from the National Project
Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni,
003” and by the RTN project “Design, Analysis and Computation
“
2
for Catalytic Organic Reactions”, contract HPRN-CT-2001-00172,
which also provided a postdoctoral fellowship to R.P.H. and D.P.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 7975 –7978
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7975

Communications
sulfones 1 furnish the corresponding imine when treated with
[
6]
a base, they have been widely used in combination with hard
[
7]
organometallic reagents or metal-stabilized enolates. The
formation of the imine in situ can also be achieved by using a
phase-transfer catalyst in combination with an inorganic base.
Despite the considerable benefits of the latter approach,
which combines the operational simplicity and the mild
[
8]
reaction conditions typical of phase-transfer catalysis (PTC)
with the convenience and the generality of the use of a-amido
sulfones 1 as imine surrogates, this reaction has been only
[
9]
occasionally reported.
Bearing in mind the impressive applications of PTC in
[
8]
enantioselective transformations, we decided to employ this
strategy in the catalytic asymmetric nucleophilic addition of
nitromethane to N-carbamoyl imines (aza-Henry reaction)
[
10]
generated in situ from a-amido sulfones 1 using cinchona-
[
11]
derived quaternary ammonium salts as catalysts. The aza-
[
12]
Scheme 1. PTC aza-Henry reaction using imine 2 and a-amido sulfone
1a.
Henry reaction,
and especially its catalytic asymmetric
[
13]
variants, has received a lot of attention in recent years, the
resulting b-nitroamines being readily converted into highly
valuable chiral compounds, such as a-amino acids and vicinal
diamines. After the first pioneering reports on metal-cata-
reaction conditions (see the Supporting Information), we
found that the reaction proceeded smoothly even at low
temperature when a stronger base, such as solid KOH, was
used, thus furnishing the product 3a directly from 1a at
À458C in good yield and with useful enantiomeric excess
(Scheme 1).
We next investigated the generality of this newcatalytic
enantioselective addition of nitromethane to N-carbamoyl
imines generated in situ from 1 by varying both the
substituent of the starting compound 1 and the protecting
group (PG) on the nitrogen atom (Table 1). A few a-amido
sulfones 1a–e derived from aromatic and heteroaromatic
[
14]
lyzed asymmetric aza-Henry reactions, a feworganocata-
[
15]
lytic protocols have been reported. Despite the remarkable
results in terms of enantioselectivity and catalytic efficiency,
all methods showa considerable limitation in the variability
of the imine partner because preformed imines are employed.
We felt that our approach could significantly extend the scope
of the reaction, besides providing a newand convenient
[
16]
protocol for this asymmetric transformation.
To test the feasibility of our approach, we thought it
convenient to first explore the capability of phase-transfer
catalysts derived from cinchona alkaloids to impart an
appreciable asymmetric induction
in the addition of nitromethane to
Table 1: Catalytic asymmetric addition of nitromethane to N-carbamoyl imines generated in situ from
a-amido sulfones 1a–l under PTC.
N-carbamoyl imines. For this pur-
pose, N-Boc imine 2a was treated in
the presence of catalytic amounts of
several cinchona-derived quater-
nary ammonium salts and KF as a
base under the solid–liquid PTC
conditions used for the enantiose-
lective addition of nitromethane to
chalcones and for the Henry reac-
[
a]
[
b]
[c]
Entry
1
R group
Ph
PG
3
t [h]
Yield [%]
ee [%]
[
e]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
Cbz
3a
3b
3c
3d
3e
3 f
3g
3h
3i
40
64
60
44
25
40
42
40
40
43
44
40
95
70
84 (>99)
[
17]
o-BrC H
76
6
4
tion (Scheme 1). Among the cat-
alysts tested (see the Supporting
Information), the commercially
available N-benzyl quininium chlo-
ride 4 proved to be the most effec-
tive, thus furnishing the correspond-
ing b-nitroamine 3a after 18 h in
good yield of isolated product and
with moderate, but promising, en-
antiomeric excess (Scheme 1).
Encouraged by this result, we
turned our attention to the possibil-
ity of using 1a directly in the
reaction with nitromethane. After
[
d]
[e]
p-MeOC H
1-naphtyl
2-furyl
75
95
81
98
84
95
92
86
53
96
88 (>99)
6
4
84
75
95
98
95
94
92
73
93
PhCH CH
2
2
Cy
iPr
Et
Me
Ph
Cy
10
11
12
1j
1k
1l
3j
3k
3l
[
f]
[f]
[
(
a] Experimental conditions: finely ground KOH (0.5 mmol) was added to a cooled mixture (À458C) of 1
0.1 mmol), 4 (0.01 mmol), and CH NO (0.5 mmol) in toluene (1 mL), and the reaction mixture
3
2
vigorously stirred for the stated time. [b] Yield of the isolated product after chromatography on silica gel.
[
[
c] Determined by chiral stationary-phase HPLC. [d] aqueous KOH (50% w/w) was used in the reaction.
e] After a single crystallization. [f] A mixture of toluene/CH Cl (1:1) was used as the solvent. Cy=
2
2
a thorough screening of different cyclohexyl.
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Angewandte
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aldehydes were treated with nitromethane under the opti-
mized reaction conditions, thus furnishing the corresponding
optically active N-Boc b-nitroamines 3a–e in fairly good yield
and enantiomeric excess (entries 1–5). It is noteworthy that
Ishitani, Chem. Rev. 1999, 99, 1069; e) A. Córdova, Acc. Chem.
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[
[
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3
a and 3c could be obtained in essentially enantiopure form
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after a single crystallization (entries 1 and 3). Moreover, we
found that this newstrategy for the catalytic enantioselective
aza-Henry reaction was particularly effective for the synthesis
of N-Boc a-alkyl b-nitroamines, which cannot be obtained by
the previously reported methods. As a matter of fact, 1 f–j,
derived from both linear and branched aliphatic aldehydes, all
gave the corresponding b-nitroamines 3 f–j in very good yields
and enantioselectivities (entries 6–10). The efficiency of the
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for by the high enantiofacial discrimination in the imine
derived from 1j (entry 10) bearing a proton and a small
methyl group. Variation of the protecting group on the
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bearing a Cbz moiety (entries 11 and 12), thus demonstrating
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protected b-nitroamines. Also in this case, 1l, derived from an
aliphatic aldehyde, gave better results with respect to 1k.
The absolute configuration of the products was deter-
mined by comparison of the HPLC retention time and optical
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2
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[
15b,c]
rotation of 3a with reported values
and by reduction of
3
h (see the Supporting Information) to the known diamine
[
18]
derivative. Attack on the Si face of the intermediate imine
by the nitronate and quininium ion pair accounts for the
R configuration at the stereogenic centre observed in both
cases.
In summary, we have developed a new catalytic enantio-
selective approach to the asymmetric nucleophilic addition of
nitromethane to N-carbamoyl imines generated in situ from
a-amido sulfones. The chiral phase-transfer catalyst acts in a
[
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under mild reaction conditions and then activating the
nucleophile for asymmetric addition. The potential of this
approach was demonstrated in the reaction of nitromethane
with a-amido sulfones, which could be efficiently catalyzed by
a simple and commercially available quininium salt. Besides
the mild reaction conditions and the operational simplicity,
this newmethod allo ws N-carbamoyl imines derived from
enolizable aldehydes in a catalytic asymmetric aza-Henry
reaction to be used for the first time, thus extending the
generality of this asymmetric transformation.
2
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Received: July 27, 2005
Published online: November 15, 2005
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Keywords: a-amido sulfones · asymmetric synthesis · aza-Henry
reaction · nucleophilic addition · phase-transfer catalysis
.
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www.angewandte.org
7977

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ii
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Angew. Chem. Int. Ed. 2005, 44, 7975 –7978