Diastereoselective addition of anisoles to: N-tert -butanesulfinyl imines via four-membered lithium cycles

Article abstract of DOI:10.1039/c8cc03764g

A highly regio- and diastereo-selective ortho-lithiation/addition of anisoles to N-tert-butanesulfinyl imines resulting in the selective formation of chiral α-branched amines is described. This method is also efficient for highly regioselective benzylic lithiation of o-methylanisoles, followed by diastereoselective addition to N-tert-butanesulfinyl imines.

Full text of DOI:10.1039/c8cc03764g

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Diastereoselective Addition of Anisoles to N-tert-Butanesulfinyl
Imines via Four-Membered Lithiumcycles.
Received 00th January 20xx,
Accepted 00th January 20xx
Leleti Rajender Reddy,* Sharadsrikar Kotturi, Yogesh Waman, Chirag Patel, Aditya Patwa and
Rajesh Shenoy.
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly regio- and diastereo- selective ortho-lithiation/addition mild conditions instead of the less stable, more expensive and
of anisoles to N-tert-butanesulfinyl imines, resulted in the highly pyrophoric t-BuLi and s-BuLi for the deprotonation at
ο
selective formation of chiral α-branched amines is described. This low temperature. The lithiation at 0 C for 1 h in the absence
method is also efficient for highly regioselective benzylic lithiation of a ligand and followed by addition to N-tert-butanesulfinyl
of o-methylanisoles and followed by diastereoselective addition aldimines 3a11 at 78 οC afforded the desired amine 7a in 90%
−
to N-tert-butanesulfinyl imines.
yield with high diastereoselectivity (>95:5) (Table 1, entry 1).
The diastereoselectivity of the reaction was determined to be
>95:5 by 1H NMR analysis of the crude product. The “>95:5” dr
denotes that signals for only one diastereomer were observed.
The structure and absolute configuration of (RS, S)-7a was
Chiral α-branched amines are highly important structural
motifs in the pharmaceuticals industry1 and are present in
many drugs, drug candidates and natural products (Figure 1).1-
6
confirmed by comparing the 1H NMR, 13C NMR, and specific
Therefore, general methods for their asymmetric synthesis
25
are of considerable importance. The stereoselective addition
of organometallic reagents to imines represents one of the
most convergent and efficient approaches. In particularly, the
diastereoselective addition of Grignard or lithium reagents to
N-tert-butanesulfinyl imines has proven to be a particularly
reliable and popular method.7 F. A. Davis and co-workers have
reported8a,b,c an elegant method of laterally lithiation of o-
tolunitrile followed by addition to N-p-tolylsulfinyl imines.
Recenlty, Rajapakse and co-workers from Merck has reported
the direct ortholithiation of N-Boc anilines followed by
addition to N-tert-butanesulfinyl imines.8d,e In this content, we
reasoned that a direct ortho lithiation of anisoles and addition
to the Davis-Ellman’s Imines to give α- branched amines, which
has not been described in the literature to the best of our
knowledge.9,10 Herein, we report a straightforward, ortho-
lithiation/addition of anisoles to N-tert-butanesulfinyl imines
via four-membered lithiumcycles. We envisaged that this
synthetic effort could be of value in a variety of research
applications, including the discovery of new bioactive
substances.
rotation data ([
25
α
]
=−52.4 (c=0.25, EtOH) with literature data
D
([
α
]
=−
51.9 (c=2.2, EtOH).12 The use of commonly available
D
amine ligands such as TMEDA, DMPU and PMDTA were not
given any advantage with respect to yield and
diastereoseletivity.
O
O
N
O
OH
OH
H
MeO
MeO
N
MeO
OMe
Lucidamine, Natural Product
Crebanine, Natural Product
H
N
OH
H
N
N
MeO
HO
NHSO2Me
OEt
PF-526014, Pfizer SNR inhibiter
BMS, beta-3 adrenergic receptor
Figure 1. α-Branched amines containing natural products and drug
candidates.
With these satisfactory reaction conditions in hand, we then
examined the flexibility of the reaction with by various aldimines
(Table 1). Interestingly, several substituted aromatic N-tert-
butanesulfinyl aldimines, such as o-chloro, p-methyl, p-methoxy
derivatives (3b−e), reacted with 5a leading to the corresponding
chiral amines (7b−e), (Table 1, entries 2-5) in excellent yields (89 –
92%) and with high diastereomeric ratios (dr 95:5). Similarly,
heterocyclic N-tert-butanesulfinyl aldimines, such as 2-furyl (3f) and
At the outset of our investigation, we chose anisole (5a) as our
model substrate. We were interested in using n-BuLi under
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2-thiophenyl (3g) smoothly reacted with 5a afforded the in 86 % yield with high diastereoselectivity (>95:5) (Scheme 2, entry
corresponding amines 7f and 7g (Table 1, entries 5, 6) in 90% and 1). To check the further scope of this conditions, treatment of 6e
92% yields respectively (dr. 95:5). Likewise, several aliphatic N-tert- with several N-tert-butanesulfinyl aldimines such as 3d, 3f, and 3k
butanesulfinyl aldimines, such as cinnamyl, isopropyl, isovaleryl, leading to the corresponding amines 8d, 8f, and 3k (Scheme 1,
entries 2−4) in excellent yields (80−90%) and good diastereomeric
derivatives (3h−j) were also reacted with 5a to form amines (7h−j)
(Table 1, entries 7-10) in yields of 82-88% with good diastereomeric
ratios (dr 90:10 to 95:5).
ratios (dr 90:10 to 95:5).
Table 1. Direct ortho-lithiation of anisole and diastereoselective
addition to various N-tert-butanesulfinyl aldimines.a
a) F. A. Davis work (ref. 8a,b,c
)
Me
S
Me
S
CN
CN
Li
LDA, THF, 78
C
THF, 78
C
+
N
O
HN
O
Me
2
R
H
R
1
entry
substrate (R)
3a: R= Ph
product
7a
yield (%)b
drc
3- -tolyl
p
NC
4-p-tolyl
1
90
91
90
89
92
90
92
82
88
84
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
90:10
>95:5
b) Rajapakse work (ref. 8d,e
)
2
3b: R= o-ClC6H4
3c: R= p-MeC6H4
3d: R= p-MeOC6H4
3e: R= p-CF3C6H4
3f: R= 2-Furyl
7b
3
7c
s-BuLi, TMEDA
H
S
NHBoc
N
O
HN
O
S
THF, 78
C
THF, 78 C
N
+
O
4
7d
O
R
Li
R
H
1a
5
7e
BocHN
2a
3
4
6
7f
C) This work
7
3g: R= 2-Thiophenyl
3h: R= Cinnamyl
3i: R= Isopropyl
3j: R= Isovaleryl
7g
S
n-BuLi,
HN
O
OMe
8
7h
THF, 78
C
S
H
O
Li
THF
0 C
N
O
+
R
9
7i
R
MeO
3
6a
7
10
7j
92:8
5a
R= Alkyl, Aryl, Heteroaryl
a
All the reactions performed with 1.0 equiv of 3, 5.0 equiv of
ο
b
S
n-BuLi,
THF
5a and n-BuLi (3.0 equiv) at 0 to −78 C for 2 h. Isolated
HN
R
O
OMe
Me
THF, 78
C
O
S
H
1
0
C
c
N
O
Li
+
yield. The diastereoselectivity was determined by H NMR
analysis. The “>95:5” dr denotes that signals for only one
diastereomer were observed.
R
OMe
3
6e
5e
R= Alkyl, Aryl, Heteroaryl
8
Scheme 1 Approaches to ortho-lithiation and asymmetric synthesis
Table 2. Addition of various areans to various N-tert-butanesulfinyl
aldimine (RS) 3d.
of amine.
To broaden the scope of this method, number of representative
directed arenes such as ethoxybenzene (5b), 2-methoxy anisole
(5c), 4-methyl anisole (5d) were also evaluated. The results are
shown in Table-2.
entry
reagent (R)
product yield (%)b
drc
1
2
3
5a: R= OMe, R2= H
5b: R= OEt, R2= H
5c: R= OMe, R2= 2-OMe, 7l
7d
7k
89
80
75
90
>95:5
>95:5
>95:5
>95:5
4
5d: R= OMe, R2= 4-Me,
7m
a
All the reactions performed with 1.0 equiv of 3, 5.0 equiv of 5 and
Figure 2. Reactive species.
n-BuLi (3.0 equiv) at 0 to −78 οC for 2 h. Isolated yield. The
diastereoselectivity was determined by 1H NMR analysis. The
“>95:5” dr denotes that signal for only one diastereomer were
observed.
b
c
Interestingly the reaction of o-methyl anisole (5e) with n-BuLi under
optimal reaction conditions selectively generated benzylic lithiation
species (6e) instead of ortho lithiation species (6a) (Figure 2). The
reaction of 6e with 3a at −78 οC afforded the amine 8a was isolated
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diastereoselective addition to various N-tert-butanesulfinyl
aldimines.
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Scheme 3. Deprotection of sulfinamide group.
In summary, we have reported the highly regioselective direct
ortho-lithiation of anisoles and followed by diastereoselective
addition to N-tert-butanesulfinyl imines via four-membered
lithiumcycles. This method is also found to be efficient for highly
regioselective benzylic lithiation of o-methylanisoles and followed
by diastereoselective addition to N-tert-butanesulfinyl imines via
five-membered lithiumcycles. Extension of this work is currently in
progress
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