Asymmetric transfer hydrogenation of ketimines using well-defined iron(II)-based precatalysts containing a PNNP ligand

Article abstract of DOI:10.1021/ol302079q

Well-defined iron(II)-based complexes containing PNNP ligands catalyze a highly enantioselective reduction of N-(diphenylphosphinoyl)- and N-(p-tolylsulphonyl)-ketimines. Under mild conditions and low catalyst loading, the ketimines are successfully reduced to the corresponding amines in enantiomeric excess ranging from 94 to 99%.

Full text of DOI:10.1021/ol302079q

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4638–4641
Asymmetric Transfer Hydrogenation
of Ketimines Using Well-Defined
Iron(II)-Based Precatalysts
Containing a PNNP Ligand
Alexandre A. Mikhailine, Mazharul I. Maishan, and Robert H. Morris*
Davenport Laboratory, Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, Ontario M5S 3H6, Canada
robert.morris@utoronto.ca
Received July 27, 2012
ABSTRACT
Well-defined iron(II)-based complexes containing PNNP ligands catalyze a highly enantioselective reduction of N-(diphenylphosphinoyl)- and
N-(p-tolylsulphonyl)-ketimines. Under mild conditions and low catalyst loading, the ketimines are successfully reduced to the corresponding
amines in enantiomeric excess ranging from 94 to 99%.
Chiral amines are commonly present in the structures of
various pharmaceuticals, agrochemicals and other bioac-
tive molecules. The importance of these molecules justifies
why so much effort is devoted to the development of
enantioselective and efficient methodologies for the synthe-
sis of enantiopure amines.1,2 The catalytic reduction of
imines using chiral transition metal complexes with mole-
cular hydrogen or cheap and safe 2-propanol as reducing
agents is one of the most environmentally benign processes
for the preparation of amines.3À5 Although various cata-
lytic systems based on Ru,6À12 Rh,12À20 Ir,12,21À27 Ti,28À30
Zn,18,31 and Cu32 were developed to be selective and
efficient for the reduction of the CdN bond, they are less
effective than the catalytic transfer- and H2-hydrogena-
tions ofCdO and CdC bonds.33 The challenges associated
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r
10.1021/ol302079q
Published on Web 08/27/2012
2012 American Chemical Society

with the reduction of imines compared to other substrates
are directly related to the intrinsic reactivity of these
molecules:34,35 they are sensitive to hydrolysis; they exist
as anti/syn and enamine isomers, as hemiaminals and
aminals when amines are present; as N,O-acetals, when
an alcohol is present; their reactivity is highly dependent on
the electronic and steric properties of the N-substituent;
and products of the reduction (amines) may deactivate the
catalyst via coordination. For this reason, the design of
catalytic systems that are efficient for the reduction of imines
with different structures is very challenging. This observa-
tion is supported by the fact that the catalytic systems are
usually sensitive to the electronics and sterics of the imines.36
This issue can be resolved if imines are modified prior to
the hydrogenation by the addition of a specific substituent
that will provide the required steric and electronic proper-
ties for the successful reduction. Corresponding amines can
be obtained when the substituent is removed (Scheme 1).
This approach has the drawback of adding extra steps to the
synthesis, but on the other hand, allows a controlled
preparation of the primary, secondary and tertiary amines
with the substituents of choice to be present in the structure.
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thetic scheme are phosphinoyl (a) and sulfonyl (b) groups.
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corresponding amines,39,45,46 which do not cause racemiza-
tion, have been reported. Catalytic systems based on plati-
num group metals, which are active and enantioselective in
the process of amine synthesis from such miscellaneous
imines, are known.14,43,45À51
Although complexes containing platinum group metals
are catalysts of choice for various catalytic transformations
because of their exceptional activities, the toxicity and low
availability of the metal make them undesirable for some
applications.52 Recently, several highly active and enantio-
selective catalytic systems for the reduction of prochiral
ketones, which are based on more abundant and less toxic
iron as a part of the catalyst, have been reported.53À58
This activity led to the discovery that the iron-containing
catalysts can also be efficiently employed for the reduc-
tion and for the reductive amination of aldehydes and
ketones.59À63
Scheme 1. Chiral Amine Synthesis from Miscellaneous Imines
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Org. Lett., Vol. 14, No. 17, 2012
4639

Importantly, a catalytic system reported by Beller and
co-workers that was generated in situ by the reaction of
(Et3NH)[HFe3(CO)11], PNNP ligand and KOH (1:3:15) in
2-PrOH for 30 min at 45 °C, can be exceptionally enantio-
selective for theasymmetrictransferhydrogenation(ATH)
of diphenylphosphinoyl imines giving the desired amine
with 29À98% enantiomeric excess (ee).60 These researchers
also demonstrated that a well-defined precatalyst (S,S)-1,
which was previously synthesized and utilized in our group
for the catalytic transfer hydrogenation of ketones,63 was
also active for the reduction of diphenylphosphinoyl imine
derived from the acetophenone, but was reproducibly less
enantioselective compared to the reaction with the catalyst
formed in situ.
Werecentlyreported a versatile one pot templatesynthe-
sis of iron(II) complexes containing various PNNP and
trans-acetonitrile or Br/CO ligands (Figure 1).64À66 These
complexes are highly active (TOF up to 30000 hÀ1) and
enantioselective (ee up to 99%) in the ATH of ketones when
activated with an excess of base at room temperature.63,67À71
In this study we report the activity and selectivity of these
precatalysts in the ATH of imines.
Figure 1. Structures of chiral complexes that were used as pre-
catalysts for the asymmetric transfer hydrogenation reactions.
Initially it was important to investigate the effect of the N-
substituent of the imine on the rate and selectivity of the
reaction. The precatalyst ((S,S)-3), which is straightforward
to make and very effective for the ATH of ketones, was
tested first for the imine reduction reactions. Imine analogs
of acetophenone were prepared using known protocols (see
the Supporting Information for details) and were subjected
to the ATH conditions. The results of the reactions are
summarized in Table 1 and show that only the imines with
bulky and strongly electron withdrawing N-substituents
such as diphenylphosphinoyl or p-tolylsulphonyl (Table 1,
entries 1À3) were successfully reduced to the correspond-
ing amines. The reduction of the imine containing the
N-diphenylphosphinoyl group is faster than the reduction
of the imine with the p-tolylsulphonyl substituent. This
indicates that both steric and electronic properties of
N-substituent are important for the successful reaction.
Exceptional enantioselectivities (up to 99%) were observed
in the reduction of both imines.
sterically demanding 1,2-diphenyl-(ethylenediamine) in the
ligand backbone derived from o-phosphinobenzaldehyde
compared to (S,S)-1 showed reproducibly higher enantios-
electivity in the formation of the amine but lower reactivity.
Complexes (S,S)-3, (S,S)-4, (S,S)-5 and (R,R)-6, which
contain PNNP ligands originating from the phosphinoalde-
hyde Ph2PCH2C(O)H and forming 5,5,5 membered rings
with the metal, were highly enantioselective, giving the
desired amine with ee from 94 to 99%. The activities of these
complexes are strongly dependent on the substituents on the
phosphorus and the type of the diamine incorporated into the
ligand backbone. Complex (S,S)-5 with electron donating
substituents (Et) on the phosphorus displayed significantly
lower activity (Table 2, entry 5) compared to the complexes
(S,S)-3 and (S,S)-4 (Table 2, entries 3, 4), which have phenyl
and p-tolyl substituents, respectively. Complexes with
ethylenediamineand 1,2-diaminocyclohexane inthe ligand
backbone were only slightly active (Table 2, entries 6, 7)
compared to the complexes with the 1,2-(diphenylethylene)
diamine (Table 2, entries 3, 4). The behavior of these
precatalyst in the reduction of imines is similar to their
reactivity in the catalytic reduction of ketones.69À71 The
stereoselective formation of one stereoisomer of the amine
over the other as expected is controlled by the stereoorienta-
tion of the diamine incorporated in the ligand backbone:
(R,R)-diamine produces (S)-amine and vise versa.
The reduction of N-(diphenylphosphinoyl)-imines was
conducted using various precatalysts (Figure 1). The results
are summarized in Table 2. Complex (R,R)-2, which contains
(63) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R. H. Angew.
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R. H. Inorg. Chem. 2008, 47, 6587–6589.
(65) Mikhailine, A. A.; Lagaditis, P. O.; Sues, P. E.; Lough, A. J.;
Morris, R. H. J. Organomet. Chem. 2010, 695, 1824–1830.
(66) Lagaditis, P. O.; Mikhailine, A. A.; Lough, A. J.; Morris, R. H.
Inorg. Chem. 2010, 49, 1094–1102.
(67) Meyer, N.; Lough, A. J.; Morris, R. H. Chem.;Eur. J. 2009, 15,
5605–5610.
(68) (a) Mikhailine, A.; Lough, A. J.; Morris, R. H. J. Am. Chem.
Soc. 2009, 131, 1394–1395. (b) Mikhailine, A. A.; Maishan, M. I.;
Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2012, 134, 12266–12280.
(69) Mikhailine, A. A.; Morris, R. H. Inorg. Chem. 2010, 49, 11039–
11044.
The activity and selectivity of the most active and en-
antioselective complex (S,S)-3 was further investigated in
the reductions of N-(diphenylphosphinoyl) ketimines with
various structures. The presence of the electron-withdrawing
and -donating substituents in the para- and meta-positions
on the aromatic ring of the ketimines has no substantial
influence on the activity and selectivity of the reaction
(Table 3, entries 1À4). The ketimine containing an ethyl
group at the imine-carbon was reduced with exceptional ee
but at a longer reaction time (Table 3, entry 5); this is
expected taking into consideration the increased steric bulk
(70) Lagaditis, P. O.; Lough, A. J.; Morris, R. H. Inorg. Chem. 2010,
49, 10057–10066.
(71) Sues, P. E.; Lough, A. J.; Morris, R. H. Organometallics 2011,
30, 4418–4431.
4640
Org. Lett., Vol. 14, No. 17, 2012

Table 1. Asymmetric Transfer Hydrogenation of N-Substituted
Imines Catalyzed by the Complex (S,S)-3a
Table 3. Asymmetric Transfer Hydrogenation of
N-(Diphenylphosphinoyl)-imines using Well-defined
Precatalyst (S,S)-3a
entry
R1
cat/sub/base time [hour] conv [%] ee [%]
1
2
3
4
5
6
-P(O)Ph2
-P(O)Ph2
-S(O)2-Tol
-Ph
1/100/8
1/300/8b
1/50/8
0.5
0.5
92
62
26
<1
<1
<1
>99 (S)
>99 (S)
94 (S)
12
1/100/8
1/100/8
1/100/8
1
1
1
-Bn
-C(O)CH3
a Conditions: mol (cat.) = 0.0045 mmol (5.89 Â10À4 M), mol (imine) =
0.45 mmol (5.89 Â10À2 M), mol (KOtBu) = 0.036 mmol (4.71 Â10À3 M),
m (2-PrOH) = 6 g; temperature = 30 °C. b mol (imine) = 1.35 mmol.
Table 2. Asymmetric Transfer Hydrogenation of
N-(Diphenylphosphinoyl)-acetopheniminea
entry
cat.
conv [%]
ee [%]
conf
1
2
3
4
5
6
7
(S,S)-1
(R,R)-2
(S,S)-3
(S,S)-4
(S,S)-5
(R,R)-6
7
99
72
94
70
11
15
17
91
96
(R)
(S)
(R)
(R)
(R)
(S)
>99
>99
>98
94
a Conditions: mol (cat.) = 0.0045 mmol, mol (imine) = 0.45 mmol,
mol (KOtBu) = 0.0036 mmol, m (2-PrOH) = 6 g; at 30 °C for 40 min.
a General conditions: mol (cat.) = 0.0045 mmol (1 mol % loading),
mol (imine) = 0.45 mmol, mol (KOtBu) = 0.0036 mmol, m (2-PrOH) =
6 g; at t = 30 °C.
of the substrate. Imines containing heteroaromatic groups
(Table 3, entries 6 and 7) were also successfully reduced with
exeptional enantioselectivities indicating that the sulfur
atom does not coordinate to the active complex. Imines
containing naphthyl substituents (Table 3, entries 8 and 9)
were reduced with high enantioselectivity. A higher catalyst
loading was required for the successful reduction of the imine
group at the 1 position of naphthalene than for one at the 2
position due to the greater steric constraints of the imine
carbon in the former compound. Low yields of the reac-
tion were obtained for the cyclic imines (Table 3, entries 10
and 11) even at high catalyst loading possibly due to the
rigidity of the imine carbon moiety. Nevertheless, the en-
antiomeric excess of the corresponding amines was high.
Inconclusion, this study shows that well-definediron(II)
complexes containing PNNP ligands, which are highly
active and enantioselective catalysts for the ATH of ke-
tones, are also active and very enantioselective for the
asymmetric reduction of N-(diphenylphosphinoyl)- and
N-(p-tolylsulphonyl)-ketimines. Specifically, precatalyst
(S,S)-3 is the most selective and active well-defined system
reported todate. The reactivity of the catalyst was found to
be very sensitive to the sterics around the imine carbon but
unresponsive toward variation of the electronic properties
of the substrate.
Acknowledgment. R.H.M. thanks NSERC for a Dis-
covery grant. A.A.M. was supported by an Ontario
Graduate Scholarship.
Supporting Information Available. General experimental
procedure that was used for the catalytic reduction of imines,
spectroscopic information and retention times observed for
different stereoisomers of the amines. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4641