Secondary amines as coupling partners in direct catalytic asymmetric reductive amination

Article abstract of DOI:10.1039/c9sc00323a

The secondary amine participating asymmetric reductive amination remains an unsolved problem in organic synthesis. Here we show for the first time that secondary amines are capable of effectively serving as N-sources in direct asymmetric reductive amination to afford corresponding tertiary chiral amines with the help of a selected additive set under mild conditions (0-25 °C). The applied chiral phosphoramidite ligands are readily prepared from BINOL and easily modified. Compared with common tertiary chiral amine synthetic methods, this procedure is much more concise and scalable, as exemplified by the facile synthesis of rivastigmine and N-methyl-1-phenylethanamine.

Full text of DOI:10.1039/c9sc00323a

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Secondary Amines as Coupling Partners in Direct Catalytic
Asymmetric Reductive Amination
Zitong Wu,a Shaozhi Du,a Guorui Gao,b Wenkun Yang,a Xiongyu Yang,a Haizhou Huang a and Mingxin
Received 00th January 20xx,
Accepted 00th January 20xx
Chang *a
DOI: 10.1039/x0xx00000x
The secondary amine participated asymmetric reductive amination remains an unsolved problem in organic synthesis. Here
we show for the first time secondary amines are capable of effectively serving as the N-sources in direct asymmetric
reductive amination to afford corresponding tertiary chiral amines with the help of selected additive set under mild
conditions (0~25 oC). The applied chiral phosphoramidite ligands are readily prepared from BINOL and easily modified.
Compared with common tertiary chiral amine synthetic methods, this procedure is much more concise and scalable, as
exemplified by the facile synthesis of rivastigmine and N-methyl-1-phenylethanamine.
www.rsc.org/
N
N
N
O
N
Introduction
S
O
selegiline
(Parkinson's disease
& depression)
Chiral amine is one of the most important classes of compounds
displaying biological activities. In fact, about 40% new chemical
entities (NCEs) among FDA approved drugs contain chiral amine
moieties.1 Tertiary amines account for 60% of the total number
of medicinal related amines (a small selection of chiral ones are
shown in Fig. 1).2 Consequently, the development of efficient
synthetic methods toward chiral amines, especially chiral
tertiary amines, remains atop the organic chemists’ priority list
and it is an intensively studied and challenging research area.3
In many cases chiral tertiary amines are prepared from the
corresponding primary or secondary amines. Among those
various methods, the protocols utilizing molecular hydrogen as
the reductant, asymmetric hydrogenation (AH) of imine/
emanine4 or iminium salts,5 and direct asymmetric reductive
amination (DARA),4a,6 are preeminently attractive due to their
high atom economy and the vast available chiral ligand pool. For
AH, in many cases imines are difficult to prepare and the
instability of them operationally complicates the following
reduction (Scheme 1, route c). Currently DARA is also taking a
circuitous route through primary amine to tertialry amine
(Scheme 1, route b) and/or the N-deprotection (Scheme 1,
route a).
rivastigmine (dementia)
OH
rotigotine
(Parkinson's disease)
F
O
OMe
N
O
F3C
N
N
Cl
S
N
clopidogrel
(anti-blood clot)
(WHO essential medicine)
CF3
N
O
orvepitant
(depression)
Fig. 1 Selected chiral tertiary amine drugs.
synthesis of pharmaceutical related and bulk fundamental
amines.8 As for DARA, since its maiden voyage in the
preparation of herbicide metolachlor,9 progress has been made
through biocatalysis,10 organocatalysis11 and transition-metal
catalysis12. This research journey is highlighted by
thesucccessful applications in the production of two
pharmaceutical drugs, sitagliptin10a and suvorexant12e
Nevertheless, compared with the prevailing utilization of achial
.
R3
NHR
NH2
deprotection
NH
R1 R2
*
R1 R2
*
R1 R2
*
Reductive amination (RA) is nature’s choice to synthesize
essential biomonomers including amino acids inside
organisms,7 and the most practical method for the aritificial
H2
X,
a
NH4
b
current ARA: detour
route
route
R3 R4
N
Our goal: DARA
direct & efficient
O
R3 R4
+
N
R1 R2
H
R1 R2
*
a. Shanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry & Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling,
Shanxi 712100, China. E-mail: mxchang@@nwsuaf.edu.cn
b. College of Chemistry, Chemical Engineering and Materials Science, Collaborative
Innovation Center of Functionalized Probes for Chemical Imaging in Universities of
Shandong, Shandong Normal University, 88 Wenhuadong Road, Jinan 250014,
China.
route
R3 R4
N+
R3 R4
N
AH
c
or
R
R1 R2
*
R1
AH: intermediate instable
Scheme 1 Routes for the synthesis of chiral tertiary amines.
Electronic Supplementary Information (ESI) available: [procedures and spectra]. See
DOI: 10.1039/x0xx00000x
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RA in both small-scale synthesis and practical industrial Evolution of chiral monodentate phosphoramidite ligand.
View Article Online
DOI: 10.1039/C9SC00323A
production, DARA lags largely behind. It requires revolutionary Initially several chiral phosphoramidite ligands (Table 2, L5a–h)
improvement in aspects of substrate scope and catalyst
reactivity to enable DARA a general tool in chiral amine
synthesis. i.e., there are no reports on secondary amine as the
N-source to construct tertiary chiral amines. If secondary
amines are successfully applied in DARA as N-sources, chiral
tertiary amines could be obtained directly without detour
(Scheme 1). The secondary amine participated RA is considered
as an challenge even in the achiral manner and typically
requires high reaction temperature (60 oC or above, even to 120
oC)8c. This difficulty probably stems from the steric congestion
during the imine/enamine formation and the reduction
thereafter. Other challenges include the formation of the
alcohol side-product resulting from ketone reduction and the
steric-control issue owing to the possible E/Z isomers of the
imine/enamine intermediates. We envisioned two strategies
may help to address those problems: (1) the addition of
appropriate additives which facilitate the imine/enamine
intermediate formation;13 and (2) the application of robust and
properly sized chiral ligands which could minimize the inhibitory
effect from the amine starting material, imine/enamine
intermediate and the amine product, and at the same time
Table 1 Initial DARA investagation of acetophenone and pyrrolidine.a
O
N
*
L
1 mol% Ir- , 50 atm H2
+
N
H
MS, 1.2 equiv. Ti(OiPr)4, 10 mol% I2
other additives, solvent, 60 oC, 24h
1a
2a
3a
PCy2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
O
Fe
O
L2
b
b
(R)-SegPhos
L3
(R)-(S)-JosiPhos
L1
(R)-BINAP
82% yield, 10% ee
61% yield, 8% ee
1) DCM, TFA 1 equiv.
25% yield, 23% ee
O
2) EtOAc, TFA 1 equiv.
69% yield, 24% ee
O
N
P
3) EtOAc, Et3N 10 mol%
72% yield, 25% ee
O
O
PAr2
O
PAr2
Ar=3,5-ditBu-
4) with Rh, EtOAc, Et3N 10 mol%
86% yield, 3% ee
5)b 80% yield, 32% ee
4-OMe-C6H2
b
L5a
(R)-PipPhos
O
1) 84% yield, 20% ee
2) with I2 1 mol%
b
L4
(R)-DTBM-GarPhos
58% yield, 25% ee
85% yield, 24% ee
a
Reaction conditions: Ir–L
1 mol%, [Ir]/L (Bisphosphine) = 1:1 or [Ir]/L
(monophosphine) = 1:2; 1a 0.2 mmol, 2a 0.2 mmol, solvent 2 mL, 60 oC, 20 h; MS
= molecular sieves, 0.1 gram; TFA = trifluoroacetic acid; I2 10 mol%; Yields and
enantiomeric excesses were determined by chiral HPLC. b EtOAc:CH2Cl2 = 1:1 was
sterically
accommodate
the
bulky
imine/enamine
intermediates. Via the proposed route, the efficiency for the
synthesis of related important tertiary chiral amine solvent with addition of 10 mol% Et3N
intermediates and active pharmaceutical ingredients (APIs)
with different structural features were synthesized and applied
would be greatly enhanced.
in the reductive coupling of 1a with 2a. It appeared the bulky
amino moiety on L5 positively impacted the enantioselectiviety:
from L5a to L5e, the ee value was improved from 24% to 60%,
then this trend reached a limit (Table 2, L5f, L5h) at around 64%
ee. So other strategy was required to further improve the
stereoselectivity. Taking full advantage of its easy modifacation
feature, we implanted the 3,3'-positions of the BINOL back-
bone with several common substituents (-Ph, -Me, -OMe and -
Results and discussion
Establishment of feasibility. Molecular sieves, Brønsted acids12d
and titanium isopropoxide12b have been proven to be efficient
additives in DARA to accelerate the formation of the imine
intermediates. At the same time molecular iodine is widely used
in asymmetric hydrogenation of imines.3b,13 So we selected
molecular sieves (MS, 4Å), titanium isopropoxide (Ti(OiPr)4),
and trifluoroacetic acid (TFA)) as the additive set with iridium–
(R)-BINAP (Table, L1) as the catalyst for the DARA of
acetophenone 1a and pyrrolidine 2a. Unfortunately the
reaction did not afford satisfying result (25% yield, 23% ee,
Table 1, L1-1). Further investigation revealed that basic Et3N
was a better additive than trifluoroacetic acid. With EtOAc and
CH2Cl2 solvent pair, the yield and ee were improved to 80% and
32% respectively. Rh–(R)-BINAP furnished much lower ee
compared with the corresponding iridium catalyst. From the
brief screening of several common chiral ligands, none of them
engendered satisfied results. Considering the BINOL-based
phosphoramidite ligands including PipPhos (Table 1, L5a) have
been widely applied in asymmetric catalysis14, and highly
attractive features of them are that their two components,
BINOL and the amino moiety, are easily assembled together,
and each part is highly modulated, we decided to focus on this
type of ligands. Exploiting the easiness of modification, we can
tailor and fine-tune their steric and electronic properties for
adapting our specific reaction.
Table 2 Examination of chiral monodentate phosphoramidite ligand in DARA of
acetophenone and pyrrolidine.a
R
R = H (L5)
Ph (L6)
OMe (L7)
Me (L8)
CH2OMe (L9)
nPr(L10)
O
N
1 mol% Ir-L, 50 atm H2
MS, 1.2 equiv. Ti(OiPr)4
1 mol% I2, Et3N 10 mol%
EtOAc:DCM 1:1, 60 oC, 24h
O
O
+
P
NR'2
N
H
1a
2a
3a
R
NR'2:
a)
b)
c)
d)
N
N
N
N
L5b: 70% yield, 4% ee
L8b: 84% yield, 78% ee
L5c: 58% yield, 29% ee
L8c: 84% yield, 78% ee
L5d: 82% yield, 30% ee
L8d: 79% yield, 76% ee
L5a: 85% yield, 24% ee
L6a: 87% yield, 0% ee
L7a: 94% yield, 57% ee
L8a: 85% yield, 87% ee
L9a: 82% yield, 88% ee
L8a:b 93% yield, 95% ee
L8a:b,c 91% yield, 95% ee
L8a:b,d 91% yield, 97% ee
L8a:b,d,e 90% yield, 96% ee
Ph
Ph
e)
f)
g)
N
N
N
Ph
Ph
L5e: 43% yield, 64% ee
L8e: 94% yield, 60% ee
L5f: 73% yield, 65% ee
L8f: 78% yield, 60% ee
L5g: 66% yield, 57% ee
L8g: 98% yield, 22% ee
N
N
N
h)
i)
j)
L5i: 75% yield, 49% ee
L8i: 68% yield, 62% ee
L10j: 65% yield, 76% ee
L5h: 60% yield, 61% ee
2 | J. Name., 2012, 00, 1-3
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a Reaction conditions: [Ir]/L/1a/2a = 1:2:100:100; 1a 0.1 mmol, solvent 2 mL, 60 oC,
20 h; MS = molecular sieves, 0.1 gram; Yields were isolated yields; Enantiomeric
excesses were determined by chiral HPLC. b 10 mol% 1,4-diazabicyclo[2.2.2]octane
(DABCO) was added instead of Et3N; reaction solvents were DCM/THF/DCE
(1:1:1.5); reaction temperature was room temperature. c The H2 pressure was 10
atm. d The reaction temperature was 0 oC. e The catalyst loading was 0.1 mol%.
results. Among the various alkylated amines, N-methylamines
are of special interest because of their role in regulating
biological functions.8c,15 We examined the DARA of 1a with N-
methylbenzylamine 2f. This particular secondary amine was
selected as the N-source because benzyl is one of the mostly
used N-protecting groups and could be easily removed with
View Article Online
DOI: 10.1039/C9SC00323A
CH2OMe) to synthesize ligands L6a–L9a. Fortunately this
approach gave rise to better results. We observed the
enantioseletivity was boosted up to 87%, in which L8a afforded
the best result (85% yield and 87% ee). The improvement
specifically functioned better for the piperidine moiety on the
chiral ligands than other groups (Table 2, L8a versus L8b–L8i).
We postulated that it stems from the rigidity of the piperidine
ring structure. While the amino moiety possesses chirality, the
steric configuration exerted significant influence on the DARA
enantioselectivity. Particularly when the 3,3'-positions of the
BINOL back-bone were embeded with substituent (Table 2, L8f
versus L8g), the ee difference was as high as 38%. Further
reaction conditions optimization enhanced the ee to 95% by
replacing 10 mol% Et3N with the same amount of 1,4-
diazabicyclo[2.2.2]octane (DABCO), solvent changed to
THF/DCM/DCE (1:1:1.5), and the reaction temperature
decreased to room temperature. We found molecular sieves
actually exerted no obviuos influence on the reaction. With 0.1
mol% of Ir–L8a under lower temperature (0 oC), the reaction still
proceeded smoothly to further improve the enantioselectivity
to 97%. When the H2 pressure was decreased to 10 atm, the
desired product was obtained without noticeable loss on yield
or stereoselectivity.
Table 3 Exploration of substrate scope.a
R3 R4
O
R3 R4
N
O
O
1 mol% Ir-(R)-L8a, 40 atm H2
+
N
H
N
P
R1 R2
1.2 equiv. Ti(OiPr)4, 1 mol% I2
DABCO 10 mol%, 4 oC, 20h
THF/DCM/DCE 1:1:1.5
R1 R2
*
1
2
3
(R)-L8a
A.
N
N
N
N
N
MeO
F
Cl
3a
3b
3c
3d
3eb
91% yield, 97% ee 88% yield, 94% ee
93% yield, 95% ee
90% yield, 96% ee
91% yield, 93% ee
N
N
N
N
N
O2N
F3C
Br
Ph
3f
3gb
3h
3ic
3j
87% yield, 92% ee
94% yield, 90% ee
89% yield, 96% ee
98% yield, 92% ee
90% yield, 92% ee
N
N
N
N
Me
N
MeO
Cl
Br
F3C
3kd
3ld
3m
3n
3ob
89% yield, 92% ee
91% yield, 93% ee
92% yield, 93% ee 91% yield, 92% ee
89% yield, 94% ee
OMe N
Cl
N
NO2
N
N
N
Examination of Substrate Scope. Under the established
optimized reaction conditions, the applicable substrate scope
with respect to both various ketones and amino coupling
partners was investigated (Table 3). The additive set and
catalytic system worked well for a series of aromatic ketones
(Table 3a). In general, the electronic property or positions of the
substituent on the aromatic ring appeared to have limited
effects on the experimental results. Regardless of whether the
ketones have para-, meta-, or ortho- aryl substituents that are
electron-donating (1c, 1k, 1p), electron-withdrawing (1d, 1e,
1h, 1i, 1n, 1r) or relatively sizeable (1g), the corresponding
products were generated in excellent yields of 87–98% and
between 90% and 97% ee Notably, sterically hindered ketones
(1o–1r, 1t), which were problematic substrates for previously
reported DARA reactions,11a,12m could be smoothly transformed
to the desired products without noticeable differences on yields
and stereoselectivity from less hindered substrates (3p versus
3c, 3r versus 3h). In addition, polar and reducible group -NO2
(3h & 3r) was well-tolerated in the reactions. Moreover, the
methodology worked fairly well for heteroaromatic ketone 1s
(91% yield and 82% ee). The aryl-alkyl hybrid ketones 1v and 1w
were not suitable substrates, as only 6% and 3% ee were
achieved for 3v and 3w respectively.
S
3se
3td
3p
3qd
3rd
97% yield, 94% ee
95% yield, 92% ee
94% yield, 97% ee
91% yield, 82% ee
95% yield, 92% ee
N
N
N
MeO
3ub,d
3v
3w
98% yield, 6% ee
95% yield, 3% ee
81% yield, 95% ee
B.
O
N
N
N
N
Ph
N
3abd,e
3ace,f
3ade,f
3aef,g
3afe,k
89% yield, 92% ee 91% yield, 92% ee
87% yield, 92% ee
89% yield, 87% ee 96% yield, 93% ee
Ph
N
N
Ph
N
N
HO
O
3age,f
3ahe,f
3aie,f
96% yield, 93% ee
3xje,k
94% yield, 91% ee
90% yield, 94% ee
96% yield, 96% ee
a
Reaction conditions: [Ir]/L8a/1a/2a = 1:2:100:110; 1a 0.3 mmol, total solvent 3
mL, 4 oC, 20 h; DABCO = 1,4-diazabicyclo[2.2.2]octane; Yields were isolated yields;
Enantiomeric excesses were determined by chiral HPLC or 1H NMR with chemical
Reaction solvents were
The applied solvents were acetonitrile/2-
methyltetrahydrofuran 1:1. e The applied ligand was (Sa, Rc)-L9i. f The additive set
b
c
shift reagent.
DMF/CH3CN/THF 1:1:1.
The applied ligand was (R)-L9a.
d
was: 10 mol% Et3N, 5 mol% I2; reaction solvents were DMF/CH3CN/THF 1:1:1;
reaction temperature was room temperature. g The applied ligand was (R)-L10j. h
Other N-sources were also successfully applied in this method
2
equiv. Ti(Oi-Pr)4 was used; 10 mol% Et3N was used instead of DABCO; reaction
solvents were CH3CN/THF 4:1; reaction temperature was 12 oC; H2 pressure was 50
atm.
(Table
3B).
Cyclic
amines,
mopholine
2b
and
tetrahydroisoquinoline 2c, coupled with 1a efficiently to afford
the desired porducts 3ab and 3ac with good yields and
enantiopurity. Acyclic amines 2d, 2e and 2f also led to satisfied
This journal is © The Royal Society of Chemistry 20xx
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various readily available reagents. The corresponding N-methyl-
N-benzyl-1-phenylethylamine product 3af was obtained in
excellent yield and enantioselectivity. Several other N-methyl
amines 2g–2j, were also explored as the N-sources and good to
excellent results were achieved. It is noteworthy that the protic
polar and acidic -OH group (1x) was well tolerated in this
methodology. To better fit substrates with different electronic
and steric properties, reaction solvents and chiral ligands have
been adjusted accordingly. Acetonitrile, a polar solvent that has
been rarely utilized in asymmetric hydrogenation, along with 2-
methyltetrahydrofuran brought better results for some meta-
and ortho-substituted, bulkier and more polar substrates 1k, 1l,
1q, 1r, 1t, 1ab and 1af than the DCM:THF:DCE solvent trio.
Dimethyl formamide, another polar solvent, also worked better
for amine sources other than pyrrolidine 2a (Table 3B). Chiral
ligand with longer side-arm L9a was applied for 1e, 1g, and 1o,
as L9i was used for various secondary amines 2b–2d and 2f–2j.
The above results have demonstrated the versatility and power
of the readily fine-tuned phosphoramidite ligand series.
A.
View Article NOnline
O
N
Ir-(R)-L8i, 50 atm H2
DOI: 10.1039/C9SC00323A
HO
HO
N
O
+
N
H
Ti(OiPr)4 2 equiv.
I2 5 mol%, Et3N 10 mol%
CH3CN/THF 1:1.5
12 oC, 20 h
O
N
Cl
1x
2 mmol
2j
4 mmol
rivastigmine
2 steps, 92% yield, 91% ee
3xj
O
B.
O
N
Ph
HN
Pd(OH)2/C, H2
HOAc, MeOH
Ir-(Sa,Rc)-L9i, 50 atm H2
Ti(OiPr)4 2 equiv.
I2 5 mol%, Et3N 10 mol%
CH3CN/THF 4:1
H
+
N
Ph
1a
2 mmol
2f
3af
4
2.4 mmol
96% yield, 93% ee
95% yield, 93% ee
12 oC, 20 h
C.
O
ref. 19
Ir-(R)-L10j, 40 atm H2
+
N
N
*
NH Ti(OiPr)4 1.2 equiv.
I2 5 mol%, Et3N 10 mol%
CH3CN/THF 4:1
1a
2c
analogue of Crispine A
r.t., 20 h
3ac
91% yield, 92% ee
D.
Ph
N
O
Ir-(Sa,Rc)-L9i 0.1 mol%, 40 atm H2
H
+
N
Ti(OiPr)4 1.2 equiv., I2 5 mol%, Et3N 10 mol%
DMF/CH3CN/THF 1:1:1 (60 mL)
r. t., 20 h
Ph
1a
10 mmol, 1.20 g
2i
10 mmol, 1.35 g
3ai, 2.29 g
94% yield, 93% ee
Scheme 2 Practical application of DARA of secondary amine to prepare tertiary
amines.
A.
Ph
O
1
Practical application. To further showcase the utility of this
DARA strategy, we next made efforts on the synthesis of
rivastigmine (API for Exelon, for the treatment of Alzheimer's
type and Parkinson's type disease and Lewy bodies, Fig. 1).
Currently its industrial production depends on racemate
N
L9i
1 mol% Ir- , 10 atm H2
Ph
+
CD3
2
N
H
DC2: 41%
1.2 equiv. Ti(OiPr)4, 5 mol% I2
Et3N 10 mol%, r.t., 20 h
DMF/THF/CH3CN 1:1:1
CD/H3
D
DC1: 7%
3ah
84% yield, 94% ee
-1a
2h
d3
B.
Ph
N
O
1
resolution.16
Several
efficient
catalytic
asymmetric
L9i
1 mol% Ir- , 10 atm D2
Ph
+
N
H
1.2 equiv. Ti(OiPr)4, 5 mol% I2
Et3N 10 mol%, r.t., 20 h
DMF/THF/CH3CN 1:1:1
DC2: 61%
CD/H3
D
2
syntheticroutes have been developed, including AH of the
corresponding ketone,17 AH of N-methyl imine11b and
asymmetric hydroamination of alkyne18 as the key
transformation. In comparison, our method is much more
efficient in terms of step-economy and operational simplicity.
Starting from readily available and cheap meta-
hydroxyacetophenone 1x, (S)-rivastigmine was synthesized
within 2 steps in 92% overall yield and 91% ee (Scheme 2A).
Moreover, with the aforementioned N-methyl benzylamine 2c
as the N-source, after N-benzyl deprotection of the resulting
product 3af from the DARA with 1a, N-methyl amine 4 could be
obtained without losing any enantiopurity (Scheme 2B). This
extended the application of this protocol to the synthesis of
chiral secondary amines. The product 3ac, from 1a and
tetrahydroisoquinoline 2c, could be further elaborated to
synthesize the analogue of the natural product and anti-tumor
alkaloid (+)-Crispine A (Scheme 2C).19 This reaction can easily be
conducted on large scales. Catalyzed by 0.1 mmol% of Ir–L9i,
the reductive amination of 1.20 g (10 mmol) of kenone 1a and
amine 2i gave 2.29 g of chiral amine 3ai (94% yield, 93% ee).
DC1: 72%
1a
2h
3ah
82% yield, 94% ee
C.
Ph
N
O
1
L9i
1 mol% Ir- , 30 atm H2
Ph
+
N
H
1.2 equiv. Ti(OiPr)4, 5 mol% I2
Et3N 10 mol%, r.t., 20 h
DMF/THF/CH3CN 1:1:1
MeOD (200 L)
DC2: 78%
CD/H3
D
2
DC1: 19%
1a
2h
3ah
67% yield, 93% ee
Scheme 3 Deuterium incorporation studies.
The above syntheses exemplify the versatility and potential
utilities of the DARA method for the expedited and
straightforward construction of important and/or medicinally
relevant enantioenriched molecules.
Mechanism study. To gain insight into the reaction pathway, we
conducted isotopic labeling experiments of 1a with 2h. From
the 1H NMR integration, using methyl deuterated substrate 1a,
the deuterium abundance on chiral center C1 of 3ah was 7%
and that on C2 was 41% (Scheme 3A). When applying deuterium
gas as the reductant, deuterium incorporations at the C1 and C2
positions were 72% and 61% respectively (Scheme 3B). The
above results indicated 1a and 2h formed the enamine
intermediate, which underwent rapid tautomerization with the
iminium form under the applied reaction conditions; also, the
hydride addition to the iridium center step in the catalytic cycle
was reversible. The results from the addition of MeOD further
confirmed the involvement of tautomerization and the
reversibility of the hydride addition in the reaction pathway
(Scheme 3C). For non-aromatic ketones 1t and 1u, two possible
enamine intermediates may be formed, along with the
E/Zisomers, resulting in inferior stereoselectivity for the
corresponding products. Although in our experiment the
Ir/ligand ratio was 1:2, the 31P NMR spectra reavealed only one
4 | J. Name., 2012, 00, 1-3
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P coordinated to Ir (see supporting information). After the Ir–
L9i complex stirred in CDCl3 with 10 equiv. of Et3N for 24 h, the
31P NMR displayed no obvious change, which excluded the
posibility of cyclometalated iridium complex formation.20 Based
on the above results, we proposed the possible reaction
pathway (Scheme 4). With the help of Ti(OiPr)4, ketone 1 reacts
with amine 2 to form the emaine intermediate int-1, which
accepts a proton and tranforms into iminium int-2. int-1 and
int-2 are under fast interconversion. The iridium(I) complex I is
oxidized to iridium(III) by molecular iodine.21 Then DABCO or
Et3N facilitates the heterolytic cleavage of the hydrogen
molecule by iridium to form III. This step is reversible, which
results in the hydrogen incorporation on C1 of 3ah (Scheme 3).
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/C9SC00323A
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21772155, 21402155 and 21602172) is gratefully
acknowledged.
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Conclusions
In summary, we have unprecedentedly applied secondary
amines as the N-sources in direct catalytic asymetric reductive
H
N
O
R
R
Ti(OiPr)4
NR2
N
N
+
HNR2
Ar
Ar
Ar
1
2
OH
+ iPrOH
int-2
int-1
Ti(OiPr)3
I
I
Cl
*P
S
I2
H2
Cl
S
*P
Cl
I
*P
S
Ir
Ir
Ir
II
I
S
H
H
N
I
N
6
7
TS
8
H
H
N
N
NR2
-
+
N
N
Ar
3
I
Cl
*P
Ir
I
S
H
III
R
N
9
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Scheme 4 Proposed reaction pathways.
amination, thus providing a solution to an important and
persisting problem in this research area. Accelerated by the
additive set and iridium-phosphoramidite ligand catalysts, they
coupled smoothly with various ketones to afford chiral tertiary
amines in excellent yields and high levels of stereocontrol.
Benefited from the highly modulated feature of the BINOL-
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structures for achieving excellent stereoselectivity. This
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protocol, related chiral tertiary amine can be synthesized in a
more convenient and effective manner.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C9SC00323A
R3 R4
Ir-L, H2
O
R3 R4
N
+
N
H
aditives, solvent
R1 R2
R1 R2
Direct asymmetric reductive amination utilizing secondary amines, the efficient tool for one-step
construction of tertiary chiral amines.