Enantioselective Hydrogenation of Activated Aryl Imines Catalyzed by an Iron(II) P-NH-P′ Complex

Article abstract of DOI:10.1021/acs.joc.9b01964

Chiral amines are key building blocks in synthetic chemistry with numerous applications in the agricultural and pharmaceutical industries. Asymmetric imine hydrogenation, particularly with iridium catalysts, is well developed. However, imine reduction still remains challenging in the context of replacing such a precious metal with a cheap, nontoxic, and environmentally friendly substitute such as iron. Here, we report that an unsymmetrical iron P-NH-P′ catalyst that was previously shown to be effective for the asymmetric hydrogenation of aryl ketones is also a very effective catalyst for the asymmetric hydrogenation of prochiral aryl imines activated with N-diphenylphosphinoyl or N-tosyl groups. The P-NH-P′ abbreviation stands for (S,S)-PPh₂CHPhCHPhNHCH₂CH₂PⁱPr₂. Density functional theory results suggest that, surprisingly, the NH group on the catalyst activates and orients the imine to hydride attack by hydrogen bonding to the PO or SO group on the imine nitrogen, as opposed to the imine nitrogen itself. This may explain why N-Ph and N-Bu imines are not hydrogenated.

Full text of DOI:10.1021/acs.joc.9b01964

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Article
Enantioselective hydrogenation of activated aryl
imines catalyzed by an iron(II) P-NH-P’ complex
Chris Sang Gyu Seo, Thibault Tannoux, Samantha A. M. Smith, Alan J. Lough, and Robert H. Morris
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01964 • Publication Date (Web): 24 Aug 2019
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Page 1 of 18
The Journal of Organic Chemistry
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Enantioselective Hydrogenation of Activated Aryl Imines Catalyzed by an Iron(II) P-NH-P’ Complex
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Chris S. G. Seo,† Thibault Tannoux,‡ Samantha A. M. Smith, † Alan J. Lough† and Robert H. Morris†*
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†Department of Chemistry, University of Toronto, 80 Saint George St., Toronto, Ont. Canada M5S 3H6.
‡ UFR Sciences et Propriétés de la Matière, Université de Rennes 1, 35042 Rennes CEDEX France.
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*rmorris@chem.utoronto.ca
Me
Me
S
Me
X
E
*
Ph
S
Ph
*
C
Ph
Ph
C
N
P
P
C
Ph
Ph
Ph
O
Ph
N
H
N
H
Ph
Ph
S
*
H
O
O
H
C
P
Ph
+ H2
H
N
Ph
C
Fe
C
O
*
Me
H
Me
O
S
S
O
S
S
H2
C
*
H
iPr
H2C
C
P
C
Ph
Ph
Ph
Ph
N
N
O
O
iPr
H
EX = SO or PPh
H
ABSTRACT: Chiral amines are key building blocks in synthetic chemistry with numerous applications in the agricultural and pharmaceu-
tical industries. Asymmetric imine hydrogenation, particularly with iridium catalysts, is well developed. However, imine reduction still
remains challenging in the context of replacing such a precious metal with a cheap, nontoxic, and environmentally friendly substitute such
as iron. Here we report that an unsymmetrical iron P-NH-P' catalyst that was previously shown to be effective for the asymmetric hydro-
genation of aryl ketones is also a very effective catalyst for the asymmetric hydrogenation of prochiral aryl imines activated with N-diphe-
nylphosphinoyl or N-tosyl groups. The P-NH-P’ abbreviation stands for (S,S)-PPh2CHPhCHPhNHCH2CH2PiPr2. DFT results suggest that,
surprisingly, the NH group on the catalyst activates and orients the imine to hydride attack by hydrogen-bonding to the PO or SO group on
the imine nitrogen, as opposed to the imine nitrogen itself. This may explain why N-Ph and N-Bu imines are not hydrogenated.
INTRODUCTION
The preparation of enantiopure amines is important for providing synthetic building blocks for bioactive molecules and chiral auxiliaries.
The asymmetric hydrogenation (AH) of imines represents one of the most direct and atom economical approaches. The significance of
asymmetric imine hydrogenation in the context of pharmaceutical and agricultural industries has been reviewed extensively.1-8 To date,
large scale AH processes have been predominantly developed with precious metal catalysts based primarily on iridium,9-12 and rhodium13
while ruthenium complexes are often used in asymmetric transfer hydrogenation (ATH) processes.10,14,15
Imines are generally challenging substrates to reduce in a stereoselective manner. They are prone to isomerization between E and Z forms.
As the amine product builds up in the AH process, it can coordinate to the metal and inhibit catalysis by preventing dihydrogen coordination.
In order to counter this, placing a bulky sulfonyl or diphenylphosphinoyl substituent on the imine nitrogen can hinder the binding of the
substrate and product amine to the metal. These groups also have the advantage of activating the imine to hydride attack by increasing the
electrophilicity of the imine carbon. The nitrogen substituent is readily cleaved to produce valuable homochiral amines.16 Thus activated
imine catalytic AH has received attention with complexes based on rhodium,16 palladium,17-21 and ruthenium.22
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Reports of the use of first row transition metal complexes for the catalytic AH of imine are limited. In 2011 Beller and coworkers reported
that a range of N-aryl substituted imines were hydrogenated to amines with ee ranging from 88 to 98% using Knölker’s iron complex
FeH(CO)2(Cp’OH) (5 mol%) in combination with the homochiral phosphoric acid (S)-TRIP (1 mol%) at 50 bar H2 and 65 °C.23 In 2014 our
group reported that an iron complex [FeBr(CO)2(L1)]BF4 with the asymmetric ligand (S,S)-PPh2CHPhCHMeNHCH2CH2PiPr2 (L1) when
activated with LiAlH4/iso-amylalcohol was active in the presence of 10 mol% KOtBu for the AH of the N-diphenylphosphinoyl imine derived
from 1-propiophenone to the amine (90% ee) at 20 atm H2 and 50 °C.24 Bai et al have described the use of homochiral cyclopentadienone)iron
complex for the AH of activated imines but the enantioselectivity was poor (ee of the amine up to 40%).25 Otherwise there have been several
reports of the ATH of activated imines by catalysts based on iron,26-29 cobalt30,31 and nickel.32
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RESULTS AND DISCUSSION
In pursuit of a highly enantioselective iron catalyst for direct hydrogenation, our group found that the iron complex FeHCl(CO)(P-NH-P’) 1
with the P-NH-P’ ligand (S,S)-PPh2CHPhCHPhNHCH2CH2PiPr2 gave superior results to complex FeHCl(CO)(L1) for the AH of aryl ketones
and was easier to synthesize.33 Here we report that the iron complex 1 permits the highly enantioselective hydrogenation of a range of
activated imines.
We chose the (E)-N-diphenylphosphinoyl imine derived from acetophenone (2a) as the model substrate, and probed various catalytic condi-
tions for hydrogenation (Table 1). An increase in the catalyst loading from 1 mol% to 3 mol% with a KOtBu loading of 10 mol% in toluene
at 80°C under 30 bar of hydrogen pressure resulted in a systematic increase in the yield of product after 20 h.(entries 2-4) Increasing the base
to catalyst ratio reduced the yield and caused a degradation in the ee (entries 1-2); this suggests that a large excess of base to catalyst may
cause undesirable side reactions. The optimal catalytic condition resulted in an 85% yield of the amine in 98.3% ee (S) (entry 4). The use of
15 bar H2 gave a slightly lower yield of amine with the identical ee, suggesting a minor dependence of hydrogen concentration on the rate
of the reaction. There was no degradation of ee in the product on going from 10 h of reaction with 64% isolated yield (entry 6) to 20 h with
85% yield (entry 4). The influence of various bases was examined (entries 7-10). Alkali metal tert-butoxides gave similar results while
catalysis with potassium hydroxide resulted in a product with a slightly degraded ee. These results suggest that the Lewis acidity of the
alkali metal cation is not a factor. No reaction was observed when potassium carbonate was used. The solvents THF and EtOH were less
effective, giving lower yields and ee (entries 11 and 12) while iPrOH gave comparable reactivity and stereoselectivity as the toluene system
(entry 13).
With the optimized reaction condition in hand, we investigated the scope of the AH with respect to the prochiral imine structures (Table 2).
In general, the substrates were reduced with high enantioselectivity (90-99%). A lower yield and ee was observed with added bulk on the
alkyl group (2a versus 2b). Substrates with a naphthyl group (2c and 2d) were reduced with exceptionally high ee of 98% and 99%. The
addition of an electron withdrawing chloro substituent at the para- or meta-position of the aryl ring (2e and 2f) resulted in a higher yield but
similar ee compared to that of an electron donating methoxy group at the para- or ortho-position (2g and 2h). Additionally, the oxygen- or
sulfur-containing heterocycle-substituted N-phosphinoylimines (2i-k) could be reduced to amines with at least 90% ee. The thiophene sub-
stituent was well tolerated; however the 5-chloro-2-thiophene and furyl derivatives underwent side reactions that resulted in a lower yield of
the amine product. Amine 3l derived from indanone was obtained in low yield and in moderate ee (79 %), and 3m, derived from 2-heptanone,
in low yield and low ee.
Next, we investigated the catalytic performance of the iron complex 1 with ketimines with various substituents on the imine nitrogen. The
AH of the N-tosylimine (4a) produced the amine in comparable yield and ee to N-phosphinoylimines. The product amine (5a) was recrys-
tallized and characterized by X-ray crystallography to reveal the absolute configuration to be (S). The cyclic N-sulfonylimine derived from
saccharine (4b) was resistant to AH and afforded a low yield of amine with low enantioselectivity. The N-phenylimine (4c) and N-butylimine
(4d) could not be hydrogenated under these conditions.
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The Journal of Organic Chemistry
Table 1. Optimization of Catalytic Conditions for the Iron-catalyzed AH of Imine 2aa
1
2
O
O
P(iPr)2
3
4
5
6
Cl
CO
PPh2
PPh2
N
HN
H
N
Fe
1
, base
H
Ph
H2
PPh2
3a
2a
Ph
1
7
8
9
entry
solvent
T (°C)
catalyst
loading
(mol%)
base
base
H2 pres-
sure
time (h)
yield (%)
ee (%)b
loading
(mol%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(bar)
30
30
30
30
15
30
30
30
30
30
30
30
30
1
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
80
80
80
80
80
80
80
80
80
80
60
80
80
1
1
2
3
3
3
3
3
3
3
3
3
3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
LiOtBu
KOH
5
20
20
20
20
20
10
20
20
20
20
20
20
20
27
11
51
85
80
64
82
84
87
0
99.3
95.6
99.0
98.3
98.3
98.3
98.3
98.3
97.7
-
10
10
10
10
10
10
10
10
10
10
10
10
3
4
5
6
7
8
9
10
11
12
13
K2CO3
KOtBu
KOtBu
KOtBu
81
73
83
97.9
97.8
98.3
EtOH
iPrOH
a The reactions were performed in duplicate with 30 bar of H2, 3.87 μmol of catalyst, 6 mL of solvent, 20 h unless specified. b Enantiomeric
excess was determined by HPLC on a chiral stationary phase.
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Table 2. Iron-catalyzed AH of N-diphenylphosphinoyl Ketimines
1
2
3
4
5
6
O
O
PPh2
O
N
PPh2
PPh2
N
N
Ar
R
2a-2k
2l
2m
O
O
7
8
9
PPh2
PPh2
O
HN
HN
H
H
PPh2
HN
Ar
R
H
(S)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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59
60
3a-3k
3m
3l
entry
Ar/R
Yield of 3
ee (%) of 3
(S)b
(%)
1
2
3
4
5
Phenyl/Me (2a)
Phenyl/Et (2b)
85
81
85
78
84
98
94
99c
98
98
1-naphthyl/Me (2c)
2-naphthyl/Me (2d)
p-chlorophenyl/Me
(2e)
6
7
8
m-chlorophenyl/Me
(2f)
81
76
74
94
96
96
p-methoxyphenyl/Me
(2g)
o-methoxyphenyl/Me
(2h)
9
2-furyl/Me (2i)
58
82
59
92
95c
90
10
11
2-thiophene/Me (2j)
5-chloro-2-thio-
phene/Me (2k)
12
13
42
14
79
35
2l
2m
a The reactions were performed with 3.87 μmol of catalyst (3 mol%), 0.0129 mmol KOtBu (10 mol%), 0.129 mmol substrate, 30 bar of H2,
6 mL of toluene, 80°C, 20 h. b Enantiomeric excess was determined by HPLC on a chiral stationary phase. c The absolute configuration was
determined to be (S) by single crystal X-ray crystallography.
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The Journal of Organic Chemistry
Table 3. Iron-catalyzed AH of N-tosyl, Cyclic N-sulfonyl and N-aryl and N-Butyl Ketiminesa
1
2
3
4
entry
1
substrate
yield (%)
82
ee (%)b
97c
O
O
S
N
5
6
7
4a
8
9
O
O
2
26
<1
55
S
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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4b
R
3,4
-
N
4c R = Ph
4d, R = Bu
a-c See the footnotes of Table 2.
In order to gain insight into the catalytic mechanism, density functional theory (DFT) calculations were performed using the M11L functional
with the inclusion of toluene solvation. The favored mechanism, as shown in an abbreviated fashion in Scheme 1, where the trans-dihydride
8 transfers a hydride to the imine in the outer coordination sphere. Complex 8 is proposed to form from the catalyst precursor 1 by the
heterolytic splitting of dihydrogen to the added base, presumably via complex [FeH(H2)L](OtBu) 7 when KOtBu is used. The heterolytic
splitting of the η2-H2 ligand via TSE produces the dihydride 8. The turnover-limiting transfer of a hydride 8 to the imine via TSA for the
phosphinoylimine (Figure 1) or TSC for the N-sulfonylimine N-1-phenylethylidene-phenylsulfonamide (imine2, Figure 2) results in the
formation of an outer-sphere, ion-paired amide complex 9 with an Fe-NH…O hydrogen bond. The NH proton remains on the nitrogen. The
amine can form by protonation of the amide by an alcohol complex [FeH(OHtBu)(CO)(P-NH-P’)]+ (Scheme 2).
A notable feature of this mechanism is the hydrogen bond formed between the N-H proton on the P-NH-P’ ligand and the P=O moiety of
the N-phosphinoyl group in TSA or a S=O moiety of the N-sulfonyl group in TSC to form an eight-membered transition state. The NH-O
interaction helps activate the imine carbon to nucleophilic attack and enhances the enantioinduction by anchoring the substrate to the catalyst.
This type of ligand-substrate interaction in activated imine hydrogenation has not been proposed previously. The closest case is the proposed
Al-O=P interaction of N-phosphinoylimines in aluminum-mediated stoichiometric reductions.34 In the previous studies of FeH2(CO)(P-NH-
P’) complexes, the enantiodetermining step in the AH of ketones was proposed on the basis of density functional calculations (DFT) to be
hydride transfer to the ketone which is hydrogen-bonded to the NH of the P-NH-P’ ligand (Figure 1, TSB).33,35 Similarly, The N-H proton is
commonly proposed to interact with the imine nitrogen and act as proton donor to unactivated imines.36-38 However the nitrogen of these
activated imines are sterically hindered and not basic. The TS structure TSG-S with the imine nitrogen of imine2 accepting a hydrogen bond
from the catalyst’s NH (Figure S5) has an energy that is 7 kcal/mol higher in energy than that of TSC-S and a TS frequency of -1150 cm-1.
This could be the explanation for the inactivity of the catalyst toward N-phenyl and N-butyl imine hydrogenation where a comparable acti-
vation is not present.
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Scheme 1. Proposed Catalytic Cycle for the Asymmetric Imine Hydrogenation Catalyzed by an Iron P-NH-P’ Complex.
1
2
Ph
3
4
5
6
PPh2
H
Ph
H
N
Fe
CO
Cl
P(iPr)2
1
7
KOtBu -KCl
8
9
Ph
Ph
PPh2
H
Ph
H
PPh2
H
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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46
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49
50
51
52
53
54
55
56
57
58
59
60
H2
H2
N
Fe
CO
N
H
Fe
CO
H
O
O
tBu
H
P(iPr)2
P(iPr)2
tBu
7
6
E=O
HN
Ar
O
H
H
TSE
HOtBu
R1
H
R1
H
N
Fe
E
Ar
H
Ph
N
N
Ar
O
E
O
N
Ph
PPh2
H
Ph
Ph
E
R1
PPh2
H
N
Fe
Fe
CO
CO
H
TSA-S
H
P
P(iPr)2
H
iPr)
or
(
2
TSC-S
R1
Ar
9
8
N
H
O
H
N
Fe
or O=S(O)Ph
O=E is O=PPh2
Similar to the ketone hydrogenation transition state TSB,33 the smaller methyl group on the substrate in TSA or TSC is pushed against a phenyl
of the PPh2 group while the larger phenyl substituent on the imine carbon is oriented toward the open side of the catalyst (Figures 1, 2). The
hydride addition results in the (S) configuration of the amine. For the imine, the aryl of the sulfonyl group or a phenyl of the OPPh2 group
fits into a gap between the PiPr2 group and the axial NH group.
Me
Ph
Me
S
S
*
*
P
Ph
C
C
N
Ph
Ph
S
O
O
S
*
H
*
H
H
H
C
C
P
Ph2
Ph
Ph
P
Ph2
Ph
Ph
H
N
H
N
C
H
Fe
H
O
C
*
C
H
Fe
H
O
C
*
S
S
iPr
iPr
iPr
iPr
H
2C
H
2C
P
C
P
C
H2
H2
TSA-S
TSB
Figure 1. The proposed transition state structure (TSA-S) for the transfer of a hydride from the dihydride complex to the activated N-phos-
phinoylimine 2a compared with that to acetophenone (TSB) to give the (S) imine or alcohol, respectively.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
Figure 2. The proposed transition state (TSC-S) for the hydride transfer from iron to imine2 (ChemDraw view and ChemCraft view with
most of the hydrogens deleted) on the basis of DFT (Gaussian09/M11L/6-31+G*/SDD for Fe/PCM toluene, ∆G‡ 34 kcal/mol relative to the
dihydride and free imine, 531i cm-1, 80 °C). Selected bond distances around the 8 membered substrate-catalyst interaction: Fe…H 1.66,
H…C 1.77, C-N 1.32, N-S 1.60, S-O 1.45, O…H 1.97, H-N 1.03, N-Fe 2.05 Å.
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
40
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43
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A complete cycle (Scheme 2) was calculated for the AH of imine2 to the amine S-PhMeCHNHSO2Ph (amine2) and the free energy profile
of the reaction is shown in Figure 3. The alkoxide complex 6 is the turn-over limiting intermediate, the lowest point in the reaction profile.
The splitting of dihydrogen to the alkoxide via TSE is a lower energy process than the hydride transfer TSC-S. Therefore the energy span of
the reaction is 27 kcal/mol, consistent with a reaction requiring a temperature above ambient. The off-cycle amido complex 15 with the
amide N-bonded to iron, as shown in the center of the cycle, is sterically hindered and is only 4 kcal/mol more stable than the outersphere
amide complex 9 and is not a stable species relative to the coordinated tBuOH complex 13 or the alkoxide complex 6 plus the amine2
product. This is not the case for the catalytic cycle involving the hydrogenation of the cyclic N-sulfonylimine 4b where the amide, when N-
bonded to iron in the amido complex 16 (Figure 4), is more stable than the alkoxide complex (plus the energies of the imine plus H2). Thus
the most stable species in the cycles are the alkoxide complex 6, or in the case of the small imine 4b, the amido complex 16. The need for
the ratio KOtBu:Fe 3.3:1 may reflect a balance between favoring the dihydrogen splitting process by an increase in concentration of the base
and inhibiting dihydrogen coordination by competitive coordination of the alkoxide to the iron in 6.
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Scheme 2. Possible Catalytic Cycle for the AH of imine2 Where the Dihydride Complex 8 Transfers a Hydride to the Imine in TSC-
S (the Turnover Limiting Transition State) and Dihydrogen is Split by an Outersphere Alkoxide Group in TSE.
1
2
3
4
5
6
7
8
Ph
Ph
O
S=O
PPh2
H
Ph
N
HOtBu
PPh2
imine2
O
O
H
H
N
Fe
CO
Ph
Ph Me
H
H
Ph
N
P
H
H
H
H
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H
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iPr)
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H
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CO
H
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P
iPr)
H
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Me
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Ph
Ph
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O
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H
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H
H
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Ph
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Ph
HOtBu
H
S=O
H
O
H
O
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Ph
Ph
Ph
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Ph
N
P
O
O
PPh2
CO
H
PPh2
CO
H
Ar
R1
Fe
Fe
H
amine2
H
(iPr)2
(iPr)2
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Figure 3. Reaction coordinate diagram corresponding to the catalytic cycle shown in Scheme 2.
Figure 4. Structure of the amido complex 16, with the amide form of (S)-amine 5b coordinated to [FeH(CO)(P-NH-P’)]+. Non-essential
hydrogens have been deleted for the sake of clarity.
Attack on the opposite face of the imine via TSA-R (Figure 5) or TSC-R (Figure S2) produces a transition state 6-7 kcal/mol higher in energy
than that of TSA-S or TSC-S; the pro-R calculated structures have the larger phenyl group against the PPh2 phenyl. Calculations of the hydride
transfer to the cyclic N-sulfonylimine 4b gave a small energy difference between pro-S (TSF-S) and R (TSF-R) transition states caused by the
more compact size of the substrate (Figure S3).
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Figure 5. Structure of the proposed pro-S transition state (at left) TSA-S (522i cm-1) and pro-R transition state (at right) TSA-R (544i cm-1)
for the hydride transfer to the N-phosphinoyl imine 2a from the FeH2(CO)(P-NH-P’) catalyst 8. Non-essential hydrogens have been deleted
for the sake of clarity. TSA-S is 29 kcal/mol relative to complex 8 plus imine or 32 kcal/mol relative to Fe-OtBu complex 6; TSA-R 38
kcal/mol.
Figure 6 shows the energy span of the reaction from the lowest energy species in the system: from the alkoxide complex 6 or the
amido complex FeHL(S-amide3) 16 to the enantio-determining hydride transfer to imine transition state (TS) for the imines, imine1 (2a)
imine2 (PhMeC=NSO2Ph) and imine3 (4b) where [FeHL]+(amide)- is 9 in Scheme 1. Thus the net reactions correspond to:
Imine1 + FeH(OtBu)L + H2  [FeHL]+(amide1)- + HOtBu (via TSA-S or TSA-R
Imine2 + FeH(OtBu)L + H2  [FeHL]+(amide2)- + HOtBu (via TSC-S or TSC-R
)
)
(1)
(2)
(3)
Imine3 + FeH(amide3)L + H2  [FeHL]+(amide3)- + amine3 (via TSF-S or TSF-R
)
The pro-S transition state for imine1 is found to be 6 kcal/mol lower in energy than the pro-R, representing a theoretical ee of 99.9% (S) ion
reasonable agreement with the experimental value of 98% ee (S). The energy span of 32 kcal/mol is consistent with the experimental
conditions where 353 K is required for the reaction to proceed. The alkoxide complex 6 was found to be lower in energy than the dihydride
complex 8 plus free HOtBu by 2.7 kcal/mol (also true for imine2 but not shown in Figure 6). Similarly the pro-S transition state for imine2
is found to be 7 kcal/mol lower in energy than the pro-R, consistent with the observed ee of 97% (S) for the amine 5a from imine 4a. The
possibility that tBuOH shuttles a proton from the catalyst NH to the imine when the hydride transfers from iron to the imine carbon was
investigated but all structures were found to be too crowded to allow the imine to approach to receive the proton. The energy span for the
more compact imine3 (4b) is determined starting from the amido complex 16 produced from a previous hydride transfer step and going to
the TSF transition states; the amido complex 16 is lower in energy than alkoxide complex 6 in this case when additional components are
added to conserve the number of atoms. No difference was calculated for the pro-R and pro-S transition states for the AH of imine3,
consistent with the low ee of 55% (S) for amine 5b which represents a ∆G of 0.8 kcal/mol, within the error range of the calculation. In all
cases the hydride transfer occurs before a proton transfer to the imine.
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TSA-R + HOtBu 38
TSA-S + HOtBu 32
34 TSC-R + HOtBu
TSF-R + amine3 26.3
TSF-S + amine3 26.0
TSC-S + HOtBu 27
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O
PPh2
N
O
O
Ph
Me
2a
S
N
O
O
S
N
4b
8 + HOtBu + imine1
6 + H2 + imine1
2.7
6+ H2 + imine2
16 + H2 + imine3
Reaction coordinate
0
Figure 6. The energy span of the catalysis for three imines, representing also the enantiodetermining hydride transfer transition state.
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An alternative route is one where dihydrogen splits heterolytically between the cationic Fe(II) center and the amide of complex 9
to reform the dihydride 8 via TSD (Figure 7) and where the outer-sphere amide form of the substrate is protonated giving the amine product
directly. The energetics of this mechanism (Figure 8) are similar to those of alkoxide mechanism (Figure 3) but now the H2 splitting step is
the turnover limiting transition state. After the precatalyst 1 is activated by KOtBu, this route may also be operational.
O
S
Me
H
Ph
O
N
Ph
H
H
H
N
Fe
TSD
]
Figure 7. An alternative transition state TSD for the heterolytic splitting of dihydrogen to the outersphere sulfonylamide.
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Figure 8. Reaction coordinate diagram (kcal/mol) for a model catalytic cycle for the asymmetric hydrogenation of imine2 catalyzed by the
FeH2(CO)(P-NH-P’) catalyst 8 where dihydrogen splits into a hydride on iron and a proton on the nitrogen of the outer sphere amide form
of the substrate. The H2 splitting transition state structure is shown with non essential atoms deleted for clarity. See also Figure S4 for the
complete cycle.
We did not find an energetically reasonable mechanism that involved the dissociation of an arm of the tridentate ligand to allow an inner
sphere hydride transfer. Inner sphere mechanisms involving dissociation of a ligand to let the bulky imine coordinate and allow hydride
migration to the imine carbon were deemed too costly energetically since they involve the breaking of an iron-phosphorus bond and then the
high transition state energy for hydride transfer in a very crowded system. The weaker iron-phosphorus bond would be the one to the
homochiral PPh2CHPh part of the ligand; the loss of this bond would likely result in poor enantioinduction. The possibility of paramagnetic
species was ruled out by calculating the energies of the S=1 and S=2 structures for the five coordinate iron complex 9, the most likely to
have an open shell. The S= 1 is 18.2 kcal/mol higher in energy than 9 with S=0, and the S=2, 30.8 kcal/mol higher in energy than 9.
CONCLUSION
We have found a well-defined base-metal precatalyst FeH(Cl)CO(P-NH-P’) 1 for the enantioselective synthesis of a range of N-phosphinoyl
and N-tosyl aryl amines by AH. This catalyst has two phenyl groups on the ligand backbone to lock a five membered ring (S,S)-
PPh2CHPhCHPhNFe into a rigid chiral array of phenyl groups to interact with the imine substrate. It enters the catalytic cycle more directly
than a previously reported [FeBr(CO)2(L1)]BF4 system that does not have a hydride or NH group and 1 is more enantioselective than the
previous version that had a more flexible ligand backbone with a smaller methyl and phenyl on the backbone. The small, cyclic imine 4b is
proposed, on the basis of DFT calculations to form a stable amido iron complex after the hydride transfer which limits turnover. The other
activated imines are bulky enough to avoid forming such a stable complex so that a tertiary-butoxide complex becomes the turnover limiting
intermediate according the calculations. The calculations revealed that the role of the oxygen of the substituent on the activated imine
nitrogen is to hydrogen bond with the N-H group of the iron catalyst and participate in anchoring the pro-S face of the C=N bond over the
hydride. The hydride transfer transition state with an eight membered -Fe-H-CNEO-HN- ring structure is turnover- and enantio-determining.
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N-phenyl and N-butyl imines were not reduced using 1 possibly because they are not electrophilic enough and cannot form this ring for
1
2
hydride transfer. This new information provides insight into ligand design for future AH catalysts.
3
4
EXPERIMENTAL SECTION
5
6
7
8
General information. All manipulations that involved air- or moisture-sensitive materials were performed using Schlenk techniques or a
glovebox under an argon or nitrogen atmosphere. All solvents were degassed and dried using standard procedures prior to all manipulations
and reactions unless stated otherwise. 39 (1S,2S)-2-(diphenylphosphino)-1,2-diphenylethylamine was purchased from ACROS Organics and
Iron catalyst 1 was prepared according to the previous literature.33 The catalyst is air sensitive as a solid and in solution. It is stable in a pure
nitrogen or argon atmosphere indefinitely. It should be weighed in a glovebox. (E)-1-Phenyl-N-tosylethanimine (4a) and 3-methyl-1,2-
benzisothiazole 1,1-dioxide (4b) were prepared using previously reported procedure by Wang and coworkers.18 (E)-N-(1-Phenylethyli-
dene)aniline (4c) was prepared from acetophenone and aniline in toluene.40 N-(1-Phenylethylidene)butylamine (4d) was prepared using
acetophenone, N-butylamine and titanium tetrachloride in diethyl ether and dichloromethane.41 Deuterated solvents were purchased from
Cambridge Isotope Laboratories, INC, and dried over activated molecular sieves. Column chromatography was performed with SiliaFlash
P60 40-63 μm silica gel from SilicycleTM.
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NMR spectra of the samples that were prepared under argon in degassed solvents were recorded at ambient temperature and pressure
1
using a Bruker Advance III 400 MHz, Agilent DD2 500 MHz or Agilent DD2 600 MHz spectrometer. H NMR spectra were internally
referenced to tetramethylsilane resonance (TMS, 0 ppm). 13C{1H} NMR spectra were referenced to solvent carbon resonances. Data for 1H
NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= broad), coupling constant (Hz), integration. Enantiomeric excesses (ee) were determined by HPLC analysis performed on an Agilent HP
1100 Series modular system operated by ChemStation LC 3D software, v.10.02. on chiral column DAICEL CHIRALPAK AD-H. Enantio-
meric purity (reported as % ee) was determined by comparison with the racemic assay and calculated as follows:
% ee = [(Area A − Area B)/(Area A + Area B)]×100.
General procedure for preparation of N-phosphinoylimines. N-phosphinoylimines were prepared using modified procedure from pre-
vious literature.42,43 A representative example is the synthesis of (S)-N-(1-phenylethyl)diphenylphosphinamide (2a). A suspension of hy-
droxylamine hydrochloride (2.78 g, 40 mmol) and sodium acetate (4.10 g, 50 mol) in 80% aqueous ethanol solution (25 mL) was stirred at
25°C for 30 minutes. Then, acetophenone (2.9 mL, 25 mmol) was added and the reaction mixture was heated to reflux for 3 hours. It was
cooled down, evaporated of all volatiles under the vacuum and the residue was put through a short silica pad. The filtrate was concentrated
in vacuo to yield crystalline oxime. It was used without further purification.
In a Schlenk flask, oxime was dissolved in a mixture of DCM and hexanes (1:1, 50 mL) and the solution was cooled down to -41°C with
MeCN/dry ice. Triethylamine (3.8 mL, 27.5 mmol) was added dropwise, followed by chlorodiphenylphosphine (4.9 mL, 27.5 mmol). The
reaction mixture was stirred overnight, concomitantly warming to room temperature. All volatiles were evaporated in vacuum and filtered
over a short pad of Celite, washed with 2x20 mL of DCM. The filtrate was extracted with 2x20 mL water and 20 mL brine and dried over
anhydrous MgSO4. The organic layer was concentrated in vacuo to afford the crude ketimine. It was purified with column chromatography
(1:1 = ethyl acetate:hexanes), and recrystallized with benzene/hexanes to yield 2a.
The characterization of N-phosphinoylimines 2a, 43 2b, 27 2c,27 2d,27 2e,43 2f,43 2g,43 2h,43 2i,44 2j,27 2k,27 2l27 and 2m26 was consistent
with those previously reported in the literature. Racemic mixture of N-phosphinoylamines were prepared by NaBH4 reduction of the respec-
tive imines.
General procedure for asymmetric reduction of imines. All of the hydrogenation reactions were performed at constant pressures using
a stainless steel 50 mL Parr hydrogenation reactor. The reactor was maintained at the appropriate temperature in oil bath. The reactor was
flushed several times with hydrogen gas at 10 bar prior to addition of catalyst and substrate solution, and base solution. In an argon glovebox,
a vial with stir bar was charged with the catalyst 1 (2.5 mg, 3.87x10-3 mmol), substrate (1.29x10-1 mmol) and 3 mL toluene. For base solution,
a separate vial was charged with KOtBu (1.4 mg, 1.29x10-2 mmol) and 3 mL toluene. The solutions were stirred for 5 minutes and transferred
to two 6 mL syringes with 12 in. needles; the needles were then stoppered well. Both syringes were taken out of the glovebox and injected
into the prepared Parr reactor against a flow of hydrogen gas. The reaction was stopped after a given amount of time by exposing it to air,
and the reactor was allowed to cool down. The catalytic mixture was filtered through a silica plug and toluene was evaporated in vacuo.
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Column chromatography (1:9:90 = triethylamine:acetone:DCM for N-phosphinoylamine, 1:10 = hexanes:ethyl acetate for N-tosylamine,
DCM for cyclic N-sulfonylamine) was performed to purify the crude mixture.
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7
(S)-N-(1-phenylethyl)-P,P-diphenylphosphinamide (3a).26 Off-white crystalline solid. Duplicate average of 35.4 mg (85% yield). 1H
NMR (400 MHz, CDCl3): δ 7.93-7.89 (m, 2H), 7.84 – 7.81 (m, 2H), 7.51 – 7.22 (m, 11H), 4.43 – 4.36 (m, 1H), 3.17 (dd, J = 9.8, 5.7 Hz,
1H), 1.58 (d, J = 6.8 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 23.69; 98% ee. Product ratio was determined by HPLC, Chiralpak AD-
H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 8.3 min (minor), 9.2 min (major).
(S)-N-(1-phenylpropyl)-P,P-diphenylphosphinamide (3b).26 Off-white crystalline solid. Duplicate average of 35.2 mg (81% yield). 1H
NMR (400 MHz, CDCl3): δ 7.88-7.85 (m, 2H), 7.77 – 7.73 (m, 2H), 7.50 – 7.14 (m, 11H,), 4.13 – 4.07 (m, 1H), 3.23 – 3.20 (dd, J = 9.7, 6.2
Hz, 1H), 2.04 – 1.98 (m, 1H), 1.87 – 1.80 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 23.66; 94% ee. Product
ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 7.5 min (minor), 9.8 min (major).
(S)-N-(1-naphthalen-1-yl-ethyl)-P,P-diphenylphosphinamide (3c).27 Off-white crystalline solid. Duplicate average of 40.9 mg (85%
yield). 1H NMR (400 MHz, CDCl3): δ 7.94-7.91 (m, 2H), 7.89 – 7.83 (m, 2H), 7.79 – 7.75 (m, 3H), 7.64 – 7.62 (m, 1H), 7.51 – 7.36 (m,
7H), 7.28 – 7.24 (m, 2H), 5.27 – 5.21 (m, 1H), 3.37 (dd, J = 9.3, 5.8 Hz, 1H), 1.70 (d, J = 6.7 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ
22.89; 99% ee. Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 9.0 min (minor), 13.2
min (major). Single crystals of this compound suitable for X-ray diffraction analysis were obtained by diffusion of hexanes into a saturated
dichloromethane solution at room temperature.
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(S)-N-(2-naphthalen-2-yl-ethyl)-P,P-diphenylphosphinamide (3d).26 Yellow crystalline solid. Duplicate average of 37.5 mg (78%
yield). 1H NMR (400 MHz, CDCl3): δ 7.95-7.91 (m, 2H), 7.85 – 7.77 (m, 5H), 7.68 – 7.64 (m, 1H), 7.51 – 7.41 (m, 7H), 7.34 – 7.31 (m,
2H), 4.60 – 4.53 (m, 1H), 3.29 (dd, J = 9.8, 5.8 Hz, 1H), 1.67 (d, J = 6.7 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.66; 98% ee.
Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 9.1 min (minor), 9.7 min (major).
(S)-N-(1-(4-chlorophenyl)ethyl)-P,P-diphenylphosphinamide (3e).26 Off-white crystalline solid. Duplicate average of 38.7 mg (84%
yield). 1H NMR (400 MHz, CDCl3): δ 7.92-7.88 (m, 2H), 7.82 – 7.78 (m, 2H), 7.52 – 7.36 (m, 6H), 7.28 – 7.21 (m, 4H), 4.41 – 4.34 (m,
1H), 3.19 (dd, J = 9.8, 5.7 Hz, 1H), 1.56 (d, J = 6.7 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 23.18; 98% ee. Product ratio was determined
by HPLC, Chiralpak AD-H column, IPA/Hex = 15:85, 1.0 mL/min, tR= 12.2 min (minor), 12.9 min (major).
(S)-N-(1-(3-chlorophenyl)ethyl)-P,P-diphenylphosphinamide (3f).45 Off-white crystalline solid. Duplicate average of 37.0 mg (81%
yield). 1H NMR (400 MHz, CDCl3): δ 7.93-7.87 (m, 2H), 7.83 – 7.77 (m, 2H), 7.53 – 7.35 (m, 6H), 7.25 – 7.14 (m, 4H), 4.42 – 4.32 (m,
1H), 3.14 (dd, J = 9.7, 5.6 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.64; 94% ee. Product ratio was determined
by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 6.1 min (minor), 8.7 min (major).
(S)-N-(1-(4-methoxyphenyl)ethyl)-P,P-diphenylphosphinamide (3g).26 Off-white crystalline solid. Duplicate average of 34.4 mg (76%
yield). 1H NMR (400 MHz, CDCl3): δ 7.91-7.88 (m, 2H), 7.84 – 7.81 (m, 2H), 7.50 – 7.34 (m, 6H), 7.24 – 7.18 (m, 2H), 6.86 – 6.80 (m,
2H), 4.38 – 4.32 (m, 1H), 3.15 (dd, J = 9.6, 5.9 Hz, 1H), 1.55 (d, J = 6.8 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.78; 96% ee.
Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 9.7 min (minor), 10.7 min (major).
(S)-N-(1-(2-methoxyphenyl)ethyl)-P,P-diphenylphosphinamide (3h).26 Yellow crystalline solid. Duplicate average of 33.6 mg (74%
yield). 1H NMR (400 MHz, CDCl3): δ 7.88 – 7.84 (m, 2H), 7.82 – 7.76 (m, 2H), 7.49 – 7.38 (m, 4H), 7.36 – 7.31 (m, 2H), 7.23 – 7.21 (m,
1H), 7.06 – 7.05 (m, 1H), 6.90 - 6.85 (m, 2H), 4.50 – 4.44 (m, 1H), 3.93 (dd, J = 11.0, 7.8 Hz, 1H), 3.75 (s, 3H, OCH3), 1.57 (d, J = 6.8 Hz,
3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.94; 96% ee. Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex =
10:90, 1.0 mL/min, tR= 22.5 min (major), 23.9 min (minor).
(S)-N-(1-furylethyl)-P,P-diphenylphosphinamide (3i).26 Yellow crystalline solid. Duplicate average of 23.4 mg (58% yield). 1H NMR
(400 MHz, CDCl3): δ 7.97-7.86 (m, 4H), 7.51 – 7.40 (m, 6H), 7.35 (dd, J = 1.9, 0.9 Hz, 1H), 6.28 (dd, J = 3.17, 1.88 Hz, 1H), 6.13 (dt, J =
3.1, 0.8 Hz, 1H), 4.45 – 4.36 (m, 1H), 3.35-3.30 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.85; 92% ee.
Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 6.9 min (major), 7.8 min (minor).
(S)-N-(1-thiophenylethyl)-P,P-diphenylphosphinamide (3j).26 Off-white crystalline solid. Duplicate average of 34.6 mg (82% yield).1H
NMR (400 MHz, CDCl3): δ 7.98-7.93 (m, 4H), 7.52 – 7.41 (m, 6H), 7.21 (dd, J = 5.0, 1.3 Hz, 1H), 6.94 – 6.91 (m, 2H), 4.62 – 4.55 (m, 1H),
3.25 (dd, J = 10.8, 5.4 Hz, 1H), 1.70 (d, J = 6.7 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.44; 95% ee. Product ratio was determined
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by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 8.6 min (major), 9.4 min (minor). Single crystals of this compound
suitable for X-ray diffraction analysis were obtained by diffusion of hexanes into a saturated dichloromethane solution at room temperature.
(S)-N-(1-(2-chlorothiophenyl)ethyl)-P,P-diphenylphosphinamide (3k).26 Yellow crystalline solid. Duplicate average of 27.7 mg (59%
yield). 1H NMR (400 MHz, CDCl3): δ 7.94-7.88 (m, 4H), 7.50 – 7.38 (m, 6H), 6.72 (d, J = 3.8 Hz, 1H) 6.66 (dd, J = 3.8, 1.1 Hz, 1H), 4.48
– 4.38 (m, 1H), 3.40 (dd, J = 10.7, 5.3 Hz, 1H), 1.62 (d, J = 6.6 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.71; 90% ee. Product ratio
was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 6.4 min (minor), 7.4 min (major).
N-(1-indanyl)-P,P-diphenylphosphinamide (3l).26 Off-white crystalline solid. Duplicate average of 17.8 mg (41% yield). 1H NMR (400
MHz, CDCl3): δ 8.04-7.95 (m, 4H), 7.70 – 7.72 (m, 1H), 7.53 – 7.44 (m, 6H), 7.24 – 7.18 (m, 3H), 4.73 – 4.63 (m, 1H), 3.24 (dd, J = 11.4,
6.4 Hz, 1H), 2.96 (ddd, J = 15.8, 8.7, 2.8 Hz, 1H), 2.80-2.72 (m, 1H), 2.65 – 2.56 (m, 1H), 2.04 – 1.94 (m, 1H); 31P{1H} NMR (121 MHz,
CDCl3): δ 22.48; 79% ee. Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 20:80, 1.0 mL/min, tR= 8.2 min
(minor), 9.4 min (major).
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N-(1-(methyl)pentylidene)-diphenylphosphinamide (3m).26 Off-white crystalline solid. Duplicate average of 5.7 mg (14% yield). H
NMR (400 MHz, CDCl3): δ 7.94 – 7.88 (m, 4H), 7.49 – 7.42 (m, 6H), 3.22 – 3.12 (m, 1H), 2.67 – 2.63 (m, 1H), 1.56 – 1.08 (m, 11 H), 0.86
(t, J = 7.1 Hz, 3H); 31P{1H} NMR (121 MHz, CDCl3): δ 22.04; 35% ee. Product ratio was determined by HPLC, Chiralpak AD-H column,
IPA/Hex = 15:85, 1.0 mL/min, tR= 9.7 min (minor), 7.3 min (major).
(S)-N-(1-phenylethyl)-4-methyl-benzenesulfonamide (5a).18 Off-white crystalline solid. Duplicate average of 29.1 mg (82% yield). 1H
NMR (400 MHz, CDCl3): δ 7.64-7.60 (m, 2H), 7.22 – 7.17 (m, 5H), 7.16 – 7.11 (m, 2H), 4.79 – 4.72 (m, 1H), 4.48 – 4.38 (m, 1H), 2.39 (s,
3H) 1.43 (d, J = 6.8 Hz, 3H); 97% ee. Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 10:90, 1.0 mL/min, tR=
12.8 min (minor), 14.1 min (major). Single crystals of this compound suitable for X-ray diffraction analysis were obtained by diffusion of
hexanes into a saturated dichloromethane solution at room temperature.
3-Methyl-1,2-benzisothiazoline 1,1-Dioxide (5b).18 Off-white crystalline solid. Duplicate average of 5.5 mg (26% yield). 1H NMR (400
MHz, CDCl3): δ 7.78 (d, J = 7.8 Hz, 1H) 7.62-7.66 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 4.83 – 4.76 (m, 1H), 4.64 (br
s, 1H), 1.63 (d, J = 6.7 Hz, 3H); 55% ee. Product ratio was determined by HPLC, Chiralpak AD-H column, IPA/Hex = 15:85, 1.0 mL/min,
tR= 12.5 min (major), 13.5 min (minor).
DFT calculations. Density functional theory calculations were performed using the Gaussian09 package46 and the M11-L hybrid functional.
All atoms were treated with the 6-31G* basis set while iron was treated with the Stuttgart effective core potential SDD. A toluene solvation
model was applied. Complete details can be found in the SI.
ASSOCIATED CONTENT
Supporting Information
The
Supporting
Information
is
available
free
of
charge
on
the
ACS
Publications
website.
A PDF file of HPLC traces of the products. X-ray crystal structures and absolute configuration determinations of 3c, 3j, and 5a. DFT
calculation details and supplementary figures. A file of the DFT calculated coordinates and energies and, in the case of transition states, the
imaginary frequency. The crystallographic cif files have been deposited as CCDC 1903117-1903119.
AUTHOR INFORMATION
Corresponding Author
*rmorris@chem.utoronto.ca
ORCID
Chris Sang G. Seo: 0000-0002-5519-4127
Robert H. Morris: 0000-0002-7574-9388
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Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
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NSERC Canada is thanked for a Discovery Grant to R. H. M. thanks NSERC Canada for a Discovery Grant and Compute Canada for an
Allocation Grant to access Sharcnet.ca.
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