Iridium-catalyzed diastereoselective amination of alcohols with chiral: Tert-butanesulfinamide by the use of a borrowing hydrogen methodology

Article abstract of DOI:10.1039/c9ob01417a

An iridium-catalyzed diastereoselective amination of alcohols with chiral tert-butanesulfinamide was developed under basic conditions, affording the optically active secondary sulfinamides in high yields and diastereoselectivities. The removal of the sulfinyl group from sulfonamides allowed a facile access to a wide range of α-chiral primary amines. This synthetic strategy was further applied in the synthesis of the marketed pharmaceuticals (S)-rivastigmine and NPS R-568.

Full text of DOI:10.1039/c9ob01417a

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DOI: 10.1039/C9OB01417A
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Iridium-Catalyzed Diastereoselective Amination of Alcohols with
Chiral tert-Butanesulfinamide by the Use of Borrowing Hydrogen
Methodology
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaomei Xi,‡a Yongjie Li,‡a Guannan Wang,a Guangda Xu,a Lina Shang,a Yao Zhang*a and Lixin Xia*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
An iridium-catalyzed diastereoselective amination of alcohols with Scheme 1. Direct amination of alcohols by using borrowing
chiral tert-butanesulfinamide was developed under basic hydrogen methodology
condition, affording the optically active secondary sulfinamides in
Although enantiopure amines are of great importance in
high yields and diastereoselectivities. The removal of sulfinyl pharmaceutical and biological chemistry,5 only a few examples of
group from sulfonamides allowed a facile access to a wide range asymmetric version of borrowing hydrogen methodology were
of α-chiral primary amines. This synthetic strategy was further developed to synthesize chiral amines.6 In 2014, Zhao group reported
applied in the synthesis of the marketed pharmaceuticals (S)- the first example of enantioselective amination of alcohols catalyzed
Rivastigmine and NPS R-568.
by an iridium complex and a chiral Brønsted acid cooperatively.7
Similar cooperative catalytic systems were then applied to not only
the dynamic kinetic resolution of β-branched racemic alcohols to
The direct amination of alcohols by using borrowing hydrogen
methodology is a highly atom economical and environmentally
benign protocol for the synthesis of amines.1,2 This redox-neutral
form
chiral
amines in
high
enantioselectivities and
diastereoselectivities,8a but also the enantioselective synthesis of 2-
substituted 1,2,3,4-tetrahydroquinolines from amino alcohols.8b
The hydrogenation or transfer hydrogenation of chiral N-tert-
butanesulfinyl imines catalyzed by various transition-metal
complexes has been long recognized as a versatile synthetic
approach to access the tert-butanesulfinyl-protected amines,9,10 and
the removal of sulfinyl group under acidic condition effectively
leads to the formation of α-chiral primary amines.11 Most recently,
process
generally
begins
with
transition-metal-catalyzed
dehydrogenative oxidation of alcohol to give an electrophilic
carbonyl compound, which is further attacked by an amine
nucleophile and then dehydrated to form imine intermediate. The
hydrogen “borrowed” by the transition-metal catalyst finally returns,
reducing imine intermediate to afford the amine product.3,4 The
overall conversion avoids using any stoichiometric reagents
(oxidants, reductant, or base) and usually generates water as the sole
by-product (Scheme 1). When we prepared this manuscript, Xiao
and coworkers reported a NaOH-catalyzed process to realize the
diastereoselective N-Alkylation of sulfinamides with racemic
alcohols.4g
Guan, Dong and co-workers reported
a
Ru-catalyzed
diastereoselective amination of racemic alcohols using chiral tert-
butanesulfinamide as the equivalent of amine nucleophiles,
providing a highly efficient way to synthesizeα-chiral amines.12
However, a number of challenges still remain in this reaction. For
instance, the reported ruthenium(II) PNP-type pincer catalyst is
hardly able to convert the sterically hindered substrates to the desired
products. To overcome the substrate limitations and improve the
reaction selectivity, we herein report an iridium-catalyzed
diastereoselective amination of alcohols with chiral tert-
butanesulfinamide.13
R
OH
R2
borrowing hydrogen methodology
[M]
HN
R1
R1
R2
[M]H2
Our studies were initiated with the optimization of reaction
conditions for racemic 1-phenylethanol 1a and (R)-tert-
butanesulfinamide 2 under Ir(III) catalysis (Table1). No desired
product was detected when [Cp*IrCl2]2 was used even if KOH was
added to promote the dehydrogenation of alcohol 1a (entries 1 and
2). On the basis of literature reports, iridacyclic complexes 4 and 5
were chosen as catalysts since they have proven highly efficient in
transfer hydrogenation of ketones,14,15 racemization of chiral
R
OH
O
RNH2
N
R1
R2
NHR
- H2O
R1
R2
R1
R2
a. College of Chemistry, Liaoning University, Shenyang 110036, China. E-mail:
zhangyao@lnu.edu.cn,lixinxia@lnu.edu.cn.
†Electronic
DOI: 10.1039/x0xx00000x
‡These authors contributed equally to this work.
Supplementary
Information
(ESI)
available.
See
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alcohols, and the synthesis of chiral 1,2,3,4-tetrahydroquinoline from yields or diastereoselectivities. However, in case of alkyl-alkyl-
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amino alcohols.8 Unfortunately, no reaction occurred in the absence
substituted alcohol 1l, the diastereoselectivity of desired product 3l
DOI: 10.1039/C9OB01417A
dropped dramatically to 4:1 because of the small size difference of
Table 2. The scope of alcohols used in amination of alcohol
Table1.Optimization of the reaction conditionsa
O
O
4
catalyst (5 mol%)
O
S
OH
S
S
O
S
5 mol % [Ir], base
OH
R2
KOH (20 mol%)
HN
R1
tBu
HN
Ph
tBu
H2N
tBu
Ph
R1
H2N
tBu
toluene, reflux, 24 h
toluene (1.5 mL)
reflux, 24 h
R2
2
1
3
2
1a
3a
drc（
RR:RS）
Entry
[Ir]
Base
-
Yieldb
NR
drc
Entry Alcohol
Product
Yieldb
80%
O
S
1
2
[Cp*IrCl2]2
-
HN
tBu
[Cp*IrCl2]2
KOH (20mol %)
-
NR
-
1
2
1a
1b
>19:1
>19:1
3a
3
4
5
4
5
4
4
4
4
4
NR
-
O
4
-
NR
-
S
HN
tBu
75%
5
KOH (20mol %)
KOH (20mol %)
NaOH (20mol %)
Cs2CO3(20mol %)
KOtBu (20mol %)
K2CO3 (20mol %)
EtONa (20mol %)
98%
< 5%
95%
95%
90%
29%
13%
>19:1
-
3b
Me
6
O
7
>19:1
>19:1
>19:1
>19:1
>19:1
S
HN
tBu
3
4
5
6
1c
1d
1e
1f
82%
71%
83%
70%
>19:1
17:1
17:1
17:1
8
3c
MeO
9
O
S
10
11
HN
tBu
3d
Cl
aReaction condition: 1a (0.6 mmol), 2 (0.5 mmol), [Ir] (5 mol %), in
a toluene (1.5 mL) at 111oC under N2 for 24 h. bYield was
determined by 1H NMR with 1,3,5-trimethoxybenzene as an internal
standard. cThe dr value was determined by 1H NMR spectroscopy of
the crude reaction mixture.
O
S
HN
HN
tBu
3e
Br
O
S
tBu
PF6
Ir
Cl
F3C
Me
3f
tBu
3g
Ir
NCMe
NH2
NH2
O
S
HN
HN
HN
Ph
Ph
4
7
8
1g
1h
1i
72%
94%
72%
50%
>19:1
>19:1
17:1
5
of base (entries 3 and 4). To our delight, desired product 3a was
obtained in 98% yield and > 19:1 dr in the presence of 20 mol % of
KOH when neutral iridacyclic complex 4 was employed as a catalyst
(entry 5).However, switching to cationic iridacyclic complex 5 led to
much lower yield. Further optimization revealed that KOH was our
best choice among different bases (entries 7-11).
With the optimal reaction conditions in hand, we next examined
the scope and generality of this transformation. The electronic effect
of the substrates was investigated by using a series of 1-
phenylethanol derivatives. The substrates bearing electron-donating
groups, such as Me or OMe, at para-or meta-position of phenyl ring
could afford the desired products (3b-3c and 3g-3h) in 72~94%
yields with excellent diastereoselectivities (>19:1 dr). The electron-
deficient substrates were also well-tolerated, yielding the
corresponding products(3d-3f and 3i) in 70%~83% yields, however,
the diastereoselectivities were slightly decreased to 17:1. Compared
O
S
tBu
3h
MeO
O
S
tBu
3i
9
Br
O
S
HN
tBu
10
1j
>19:1
3j
O
S
HN
tBu
11
12
13
1k
1l
75%
70%
84%
>19:1
4:1
3k
O
S
HN
tBu
with
the
reported
ruthenium(II)
PNP-type
pincer
catalyst,12iridacyclic complex 4 exhibits a relatively higher catalytic
reactivity for the sterically hindered substrates. For example,1j,
having methyl group at the ortho-position of phenyl ring, could be
successfully converted to 3j in 50% yield with high dr (>19:1 dr).
Notably, this catalytic system could also be applied to the ethyl-
substituted substrates, affording 3k without significant decrease in
3l
O
S
HN
tBu
1m
17:1
3m
N
2 | J. Name., 2012, 00, 1-3
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aReaction condition: 1a (0.6 mmol), 2 (0.5 mmol), 4 (5 mol %), in
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DOI: 10.1039/C9OB01417A
b
c
toluene (1.5 mL) at 111oC under N2 for 24 h. Isolate yield. The dr
value was determined by 1H NMR analysis.
β-substituents. In order to expand the substrate scope, we have also
explored racemic alcohols containing heteroatoms, resulting in chiral
pyridine derivatives (3m) in 84% yield with high diastereoselectivity
(17:1 dr). Additionally, when the same set of reaction conditions
used in Table 2 is applied to 1h and (S)-tert-butanesulfinamide, 3h’
could be obtained in good yield and excellent diastereoselectivity
(eq. 1).
Conclusions
In conclusion, we developed a novel Ir-based catalytic system for the
diastereoselective amination of alcohols with chiral tert-
butanesulfinamide. A wide range of optically active secondary
sulfinamides were obtained from racemic alcohols in good to high
yields with excellent diastereoselectivities. This catalytic system
enabled us to accomplish the synthesis of marketed pharmaceuticals
(S)-Rivastigmine and NPS R-568.
O
4
(5 mol %)
OH
S
O
S
HN
tBu
KOH (20 mol %)
MeO
eq. 1
MeO
H2N
tBu
toluene (1.5 mL)
reflux, 24 h
Conflicts of interest
1h
3h',
94%, >19:1 dr
The authors declare no competing financial interest.
To further highlight the application of iridium-based catalytic
system, it was utilized in the synthesis of (S)-Rivastigmine,16 an
acetylcholinesterase inhibitor which is generally used to treat the
dementia caused by Alzheimer’s or Parkinson’s disease. The
removal of sulfinyl group in 3h’ under acidic condition was carried
out to form the α-chiral amine (S)-6 in 93% yield and 99%ee.
Subsequently, N, N-dimethylation of (S)-6 with access amount of
formic acid and formaldehyde yielded 7, which was then converted
to 8 in 92% yield by removing O-methyl group in the presence of
aqueous HBr. Finally, the carbamoylation of 8 with commercially
Acknowledgements
The NSFC (grant No. 21502082, 21671089), the Natural Science
Foundation of Shenyang (F16-103-4-00), and Scientific Research
Fund of Liaoning Province (LT2017010, 20170540409) are
gratefully acknowledged.
Notes and references
available
N-ethyl-N-methylcarbamoylchloride
afforded
(S)-
Rivastigmine (> 99% ee) in 64% overall yield after recrystallization
(Scheme 2). Similarly, the synthesis of NPS R-568,17 which is a type
II calcimimetic compound of pharmaceutical importance, could be
realized in 63% overall yield and 99% ee (Scheme 3) by removing
sulfinyl group in 3h, followed by reductive amination with 10.
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O
1) HCHO, HCOOH
90 oC, 1 h
2) HCHO, 90 oC, 26 h
S
NH2
HN
tBu
HCl in dioxane
MeO
MeO
MeO
MeOH, rt, 0.5 h
93% yield
81% yield
-6
(S) , 99% ee
3h'
N
N
Cl
N
HBr
N
100 oC, 12 h HO
92% yield
N
O
O
NaH, THF
93% yield
O
9
(S)-Rivastigmine
8
7
64% overall yield
Scheme 2. Synthesis of (S)-Rivastigmine from 3h’
O
H
1)
O
10
MeOH, reflux, 7 h
2) NaBH4, 72% yield
Cl
S
NH2
HN
HN
tBu
HCl in dioxane
MeO
MeO
MeO
MeOH, rt, 0.5 h
90% yield
-6,
(R) 98%
3h
ee
Cl
11
NPS R-568
63% overall yield
Scheme 3. Synthesis of NPS R-568 from 3h
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