Dicationic [(BINAP)Pd(solvent)2]2+[TfO-]2: Enantioselective hydroamination catalyst for alkenoyl-N-oxazolidinones

Article abstract of DOI:10.1039/b302246c

Dicationic (BINAP)palladium(II) complex induced high enantioselectiviies in the addition of primary (and secondary) aromatic amines to α, β-unsaturated oxazolidinones (up to 93% ee).

Full text of DOI:10.1039/b302246c

Dicationic [(BINAP)Pd(solvent)2]2+[TfO2]2: enantioselective
hydroamination catalyst for alkenoyl-N-oxazolidinones
Kelin Li and King Kuok (Mimi) Hii*
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK.
E-mail: mimi.hii@kcl.ac.uk; Fax: +44 20 7848 2810; Tel: +44 20 7848 1183
Received (in Cambridge, UK) 27th February 2003, Accepted 20th March 2003
First published as an Advance Article on the web 8th April 2003
Dicationic (BINAP)palladium(II) complex induced high
enantioselectiviies in the addition of primary (and secon-
dary) aromatic amines to a, b-unsaturated oxazolidinones
(up to 93% ee).
Herein, we report results from the study of the activity and
selectivity of catalyst 1 in the addition of aromatic amines,
including the first examples of enantioselective addition of
primary aromatic amines, to a,b-unsaturated oxazolidinones 2
(Scheme 2).
The hydroamination (HA) reaction involves the addition of an
N–H bond across a double or triple bond, furnishing valuable
nitrogen-containing molecules from readily available and non-
hazardous precursors with 100% atom economy, making it one
of the most desirable processes, economically and environmen-
tally. Alkenes containing electron-withdrawing substituents
(e.g. CO2R, CN) are more susceptible to nucleophilic attack by
alkyl amines, and these so-called aza-Michael addition reac-
tions may occur in the absence of catalysts. Nonetheless, in
many cases (e.g. disubstituted alkenes, non-nucleophilic aro-
matic amines), the reaction has an unfavourable DG0 and gave
poor yields, even at extremely high reaction temperatures and
pressures.1
Much of the development of catalysts for the HA reaction
were largely concerned with overcoming this energetic barrier.2
With prochiral alkenes, the reaction poses further synthetic
challenges in regio- and stereoselectivity. Catalytic enantiose-
lective HA reactions have been achieved by late transition metal
complexes of nickel,3,4 palladium5 and iridium6 in recent years.
However, these catalysts are somewhat specific to the type of
substrates, and the reactions still require excessively long
reaction times/high catalytic loadings.
Table 1 displays the results of the addition of a number of
aromatic amines to alkenoyl oxazolidinones 2a–c, catalysed by
complex 1.
The addition of primary aromatic amines to crotonyl
oxazolinidnone 2a occurred readily at rt. In all cases, very good
conversions (85–96%) were obtained in a relatively short period
of time (18 h), compared to other enantioselective HA catalytic
reactions. Among the different primary amines, the addition of
aniline proceeded with the highest ee (93%, entry 1).9
Interestingly, the presence of an electron-withdrawing Cl
substituent did not appear to alter the yield or selectivity
significantly (entry 2), whereas the addition of increasingly
electron-rich amines such as p-tolylamine and p-anisidine
reduced the ee to 73 and 37% respectively (entries 3 and 4).
In light of these results, the addition of the sterically and
electronically demanding N-methyl aniline confounded our
expectations. Under the same reaction conditions, it afforded
the product in unexpectedly high yield and ee (Table 1, entry 5).
The result is comparable to that achieved previously by Ni(II
)
Our contribution to the catalytic HA chemistry includes a
class of palladium(II) thiocyanate complexes that catalyse the
addition of aromatic and aliphatic amines to cyclic dihydrofuran
and pyran rings under pH neutral conditions.7 Subsequently, we
reported cationic (diphosphine)palladium(II) complexes that are
capable of facilitating the addition of a range of amines to
acyclic alkenes (styrene, crotonates, cinnamates and acrylates)
at low catalytic loadings (0.25 mol%, 400 turnovers).8 We also
described the preparation and characterisation of dicationic
(BINAP)palladium(II) complex 1, which catalysed the re-
giospecific addition of aniline to styrene, in 75% yield and 70%
ee, with just 2 mol% catalytic loading (Scheme 1).
Scheme 2 Addition of aromatic amines to a,b-unsaturated oxazolidinones
2.
Table 1 Addition of aromatic amines to a,b-unsaturated oxazolidinones
Entry
R1
Amine
T/°C
Yield (%)a
eeb
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Et
Et
Et
Et
Pr
PhNH2
25
25
25
25
25
60
60
60
25
60
60
60
93
96
85
89
75
66
95
94
52
72
77
68
93
90
73
37
87c
41
55
32
3
4-Cl–C6H4NH2
4-Me–C6H4NH2
4-MeO–C6H4NH2
PhNHMe
PhNH2
4-Cl–C6H4NH2
4-Me–C6H4NH2
4-MeO–C6H4NH2
PhNH2
4-Cl–C6H4NH2
4-Me–C6H4NH2
10
11
12
27
33
ndd
Pr
Pr
a Reactions were conducted in toluene with 10 mol% catalyst 1 for 18 h.
Calculated by 1H NMR spectroscopy. b Determined by chiral HPLC (Daicel
Chiralpak AD). c Determined by chiral HPLC (Daicel Chiracel OD-H).
d Not determined, enantiomers cannot be resolved.
Scheme 1 Enantioselective addition of aniline to styrene catalysed by
complex 1.
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CHEM. COMMUN., 2003, 1132–1133
This journal is © The Royal Society of Chemistry 2003

complex of a chiral bis(oxazolidine) ligand DBFOX-Ph (5
mol% catalytic loading, rt, 40 h, 62% yield, 90% ee).3 We are
not able to explain this result at this particular juncture, suffice
to say that the selectivity of the reaction is obviously dictated by
a number of delicately balanced steric and electronic parame-
ters.
Changing the substituent of the alkenoyl functionality has a
dramatic effect on the rate of the reactions. The addition of
primary aromatic amines to pentenoyl oxazolidinone 2b was
considerably slower at rt. Performing these reactions at an
elevated temperature (60 °C), moderate ee’s of 41% and 55%
were obtained for aniline and 4-chloroaniline respectively
(entries 6 and 7), compared with the more electron rich
4-tolylamine (32% ee, entries 8). The addition of the more
nucleophilic para-anisidine may be effected at rt, but there was
virtually no enantioselectivity (entry 9).
mol%), the reactions proceeded in high yields under a relatively
short period of time. This has given us sufficient impetus to
explore other cationic transition metal catalysts, as well as
matching substrates, in stereoselective HA reactions. The
results of these studies will be reported in due course.
We are grateful to EPSRC for a ROPA grant (GR/R50332/
01) and the industrial sponsors who helped realise this award
(Synetix, ICI and Aventis Pharmaceuticals). HPLC equipment
was procured through the generosity of The Royal Society,
Aventis Pharmaceuticals and King’s College London. Palla-
dium salts are obtained through a loan agreement with Johnson
Matthey plc.
Notes and references
1 Recent reviews in this area: (a) M. Beller, C. Breindl, M. Eichberger, C.
G. Hartung, J. Seayad, O. R. Thiel, A. Tillack and H. Trauthwein,
Synlett, 2002, 1579; (b) M. Nobis and B. Driessen-Holscher, Angew.
Chem., Int. Ed. Engl., 2001, 40, 3983; (c) T. E. Müller and M. Beller,
Chem. Rev., 1998, 98, 675.
Extending the homology, the addition of the primary
aromatic amines to hexenoyl oxazolidinone 2c proceeded in
even lower selectivities (entries 10–12).
Amination mechanisms involving alkene and/or amine
activation have been proposed, particularly in the HA of less
activated alkenes such as styrenes and norbornene.6,10 How-
ever, since complex 1 failed to induce any reaction between
aniline and methyl crotonate (even at 60 °C), we believe that the
cationic palladium catalyst is probably acting as a chiral Lewis
acid in these systems. The unsaturated double bond is activated
towards attack by the weak nitrogen nucleophile by the
chelation of the oxazolidinone functionality to the metal centre
(Fig. 1), which also bestows stereodifferentiation to the process.
A very similar reaction intermediate has been previously
proposed by Jørgensen.3
In this communication, we have demonstrated that [(BI-
NAP)Pd]2+ complex 1 is able to catalyse HA reactions between
primary and secondary aromatic amines and alkenoyl ox-
azolidinones enantioselectively, under pH neutral conditions.
Even though the catalytic loading used was quite high (10
2 D. M. Roundhill, Catal. Today, 1997, 37, 155.
3 W. Zhuang, R. G. Hazell and K. A. Jørgensen, Chem. Commun., 2001,
1240.
4 L. Fadini and A. Togni, Chem. Commun., 2003, 30.
5 M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 2000, 122, 9546.
6 R. Dorta, P. Egli, F. Zurcher and A. Togni, J. Am. Chem. Soc., 1997,
119, 10857.
7 X. Cheng and K. K. Hii, Tetrahedron, 2001, 57, 5445.
8 K. Li, P. N. Horton, M. B. Hursthouse and K. K. Hii, J. Organometallic
Chem., 2003, 665, 250.
9 Typical reaction procedure: 22 mg (0.020 mmol) of complex 1 and
3-(E)-2-butenoyl-1,3-oxazolidin-2-one (46 mg, 0.30 mmol) were placed
into a thick-walled Young’s tube. 1.0 mL of toluene and aniline (20 µL,
0.20 mmol) were added via syringe. The tube was sealed via a PTFE tap
and the reaction mixture was stirred at rt for 18 h. Conversion was
monitored by 1H NMR spectroscopy (93%). The ee (93%) was
determined by HPLC using a Chiralpak AS column (hexane:iPrOH =
80+20; tr(major) = 14.6 min, tr = 19.3 min). The homogeneous red
solution was subjected to column chromatography (SiO2, EtOAc+hex-
ane, 1+2) to furnish the product, which was recrystallised from
20
EtOAc+hexane to give a white solid. [a]D = + 8.2° (c = 0.018,
CHCl3, 86% ee). 1H NMR (CDCl3): d 7.15 (t, 2H, J = 8.6 Hz), 6.69 (t,
1H, J = 7.3 Hz), 6.62 (d, 2H, J = 8.6 Hz), 4.25–4.37 (m, 2H), 4.06–4.17
(m, 1H), 3.84–3.96 (m, 2H), 3.79 (br s, 1H), 3.35 (dd, 1H, J = 15.0, 7.3
Hz), 3.01 (dd, 1H, J = 15.0, 5.5 Hz), 1.30 (d, 3H, J = 6.4 Hz). 13C {1H}
NMR (CDCl3): d 172.1, 154.0, 147.2, 129.6, 117.9, 113.9, 62.3, 46.7,
42.9, 41.8, 21.6.
10 U. Nettekoven and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124,
1166.
Fig. 1 Proposed catalytic intermediate.
CHEM. COMMUN., 2003, 1132–1133
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