Diastereoselective Electrophilic α-Hydroxyamination of N-tert-Butanesulfinyl Imidates

Article abstract of DOI:10.1021/acs.orglett.6b03835

Diastereoselective α-hydroxyamination of N-tert-butanesulfinyl imidates using nitrosoarenes is reported. A catalytic amount of base effectively promotes the hydroxyamination reaction of α-aryl-substituted imidates, and the resulting α-hydroxyamino imidates can be transformed into a range of synthetically useful intermediates.

Full text of DOI:10.1021/acs.orglett.6b03835

Letter
pubs.acs.org/OrgLett
Diastereoselective Electrophilic α‑Hydroxyamination of N-tert-
Butanesulfinyl Imidates
Peng-Ju Ma,†,‡ Hui Liu,† Chong-Dao Lu,*,† and Yan-Jun Xu*,†
†Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese
Academy of Sciences, Urumqi 830011, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Diastereoselective α-hydroxyamination of N-tert-butanesulfinyl
imidates using nitrosoarenes is reported. A catalytic amount of base effectively
promotes the hydroxyamination reaction of α-aryl-substituted imidates, and the
resulting α-hydroxyamino imidates can be transformed into a range of
synthetically useful intermediates.
nantioselective construction of C−N bonds is attractive
Scheme 1. Nucleophilic Reactions of N-tert-Butanesulfinyl
Imidates
E
because of the ubiquity of chiral amines in bioactive natural
products and pharmaceuticals. Numerous synthetic approaches
have been developed, including nucleophilic substitution,
reductive amination, nucleophilic addition to CN double
bonds, transition-metal-catalyzed cross-coupling, and electro-
philic amination.1 A particularly straightforward asymmetric
approach toward optically active amino acid derivatives is direct
electrophilic amination of chiral metal enolates using suitable
nitrogen sources. In 1986, the Evans and Vederas groups
succeeded in using dialkyl azodiformates to aminate enolates
derived from chiral carboximides,2 and subsequently, this
strategy has been used to aminate several other chiral variants.3
Chiral amines are often constructed using tert-butanesulfina-
mide, as first shown by Ellman and co-workers, in a process
involving diastereoselective nucleophilic addition to N-tert-
butanesulfinyl (N-tBS) imines.4 The corresponding nucleophilic
addition of enolizable N-tBS imines has met with limited
success,5 in part because of a competing self-condensation
reaction that occurs at the enolization step in the presence of
bases.6 Replacing N-tBS imines with N′-tBS amidines or N-tBS
imidates can avoid this problem, allowing C−C bond formation
in such reactions as alkylation,7 Mannich addition,8 and Michael
addition (Scheme 1).9 Aldolization is also feasible when
TiCl2(OiPr)2/Et3N is used because this species simultaneously
promotes enolization and suppresses the reverse reaction of aldol
condensation.10
(Table 1). After 1a was deprotonated using lithium diisopropy-
lamide (LDA), the reaction proceeded smoothly to provide α-
hydroxyamino imidate 3a in 65% yield and 3:1 dr (entry 1). The
desired α-hydroxyamination product was obtained exclusively,
with no formation of oxygenation product via the O-addition
pathway.13 The same diastereoselectivity was observed when
LiHMDS was used as a base (entry 2). The diastereoselectivity
was reversed (1:1.4 dr) by adding 1.2 equiv of hexamethylphos-
phoramide (HMPA) to the reaction, but conversion of only
∼40% was observed (entry 3). Reducing the amount of HMPA
to 0.20 equiv reversed the diastereoselectivity again (1.4:1 dr)
and increased the conversion to ∼85% (entry 4). Increasing the
amount of HMPA to 6.0 equiv completely suppressed the
reaction. Replacing LiHMDS with NaHMDS improved dr to
>20:1 and yield to 81% (entry 5). KHMDS can also initiate the
reaction: it gave high dr but lower yield (67%, entry 6). Similarly
high diastereoselectivity was obtained using NaHMDS as a base
To our knowledge, diastereoselective C−N bond formation
using N-tBS imidates has not been reported. Here, we show that
aza-enolates derived from N-tert-butanesulfinyl imidates can be
intercepted by using aromatic nitroso compounds11 as electro-
philes. This allows highly diastereoselective construction of α-
hydroxyamino N-tert-butanesulfinyl imidates.12
Initially, we screened various bases to promote the
hydroxyamination reaction of metallo aza-enolate derived from
(RS)-N-tert-butanesulfinyl imidate 1a with nitrosobenzene (2a)
Received: December 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03835
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Table 1. Initial Attempts to α-Hydroxyaminate N-tert-
Butanesulfinyl Imidates
Table 2. Substrate Scope of the α-Hydroxyamination of N-
tert-Butanesulfinyl Imidates
a
a
nitrosoarenes
(Ar)
yield
b
c
entry
imidate (R)
1a (Me)
product
(%)
dr
b
c
entry base (equiv)/HMPA (equiv) imidate product (yield)
dr
1
2
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
3a
3b
3c
3d
3e
3f
81
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1
2
3
4
5
6
7
8
9
LDA (1.2)
1a
1a
1a
1a
1a
1a
1e
1e
1e
1a
3a (65%)
3a (78%)
3:1
3:1
1b (Et)
76
81
80
LiHMDS (1.2)
LiHMDS (1.2)/1.2
LiHMDS (1.2)/0.20
NaHMDS (1.2)
KHMDS (1.2)
e
3
1c (Pr)
d
d
e
3a (ni)
1:1.4
4
1d (Bn)
e
3a (ni)
1.4:1
f
5
1e (Ph)
85 (76)
87
3a (81%)
3a (67%)
3e (65%)
3e (85%)
3e (80%)
>20:1
>20:1
>20:1
>20:1
>20:1
6
1f (4-MeC6H4)
1g (3-MeC6H4)
1h (2-MeC6H4)
e
7
3g
3h
3i
45
NaHMDS (1.2)
NaHMDS (0.20)
LiHMDS (0.20)
NaHMDS (0.20)
8
79
88
64
81
76
9
1i (4-MeOC6H4) 2a (Ph)
10
11
12
1j (4-BrC6H4)
1k (4-FC6H4)
2a (Ph)
2a (Ph)
2a (Ph)
3j
e
f
10
3a (ni)
na
3k
3l
a
Reaction conditions: 1 (0.30 mmol), 2a (0.39 mmol), and base in
anhydrous THF (3.0 mL) under argon at −78 °C; the reaction was
complete within 30 min, unless otherwise noted. Isolated yield after
silica gel chromatography. Determined by H NMR spectroscopy of
the crude reaction mixture. Reaction mixture was stirred for 3 h
before quenching. Not isolated. Not analyzed. Since TLC analysis
indicated most of the starting material 1a was intact, no NMR analysis
of the crude reaction mixture to determine diastereoselectivity was
conducted.
1l (3,4-
diClC6H4)
b
d
13
14
15
16
17
18
19
ent-1a (Me)
2a (Ph)
ent-3a
ent-3e
3m
75
71
80
80
60
62
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
5:1
c
1
d
ent-1e (Ph)
2a (Ph)
d
1a (Me)
1a (Me)
1a (Me)
1a (Me)
1a (Me)
2b (3-MeC6H4)
2c (2-MeC6H4)
2d (4-ClC6H4)
2e (4-BrC6H4)
e
f
3n
3o
3p
e
2f (4-
MeOC6H4)
3q
76
20
21
22
23
24
1e (Ph)
1e (Ph)
1e (Ph)
1e (Ph)
1e (Ph)
2b (3-MeC6H4
2c (2-MeC6H4)
2d (4-ClC6H4)
2e (4-BrC6H4)
3r
3s
3t
82
90
68
68
>20:1
>20:1
>20:1
17:1
and α-phenyl-substituted imidate 1e as substrate (entry 7),
although the yield of the corresponding α-hydroxyaminination
product 3e was only 65%, reflecting a competing reaction in
which adduct 3e was dehydrated under basic conditions to afford
the corresponding N-phenyl α-imino imidate.14
3u
3v
e
2f (4-
MeOC6H4)
69
>20:1
This side reaction could be suppressed using a catalytic
amount of base. The hydroxyamination reaction of 1e could be
effectively promoted using 0.20 equiv of NaHMDS, which led to
higher yield (85%, entry 8) than a stoichiometric amount of base
(65%, entry 7). In fact, 0.20 equiv of LiHMDS was also effective,
giving 3e in 80% yield with excellent stereocontrol (entry 9).
However, a catalytic amount of base was not sufficient for
hydroxyamination of α-alkyl-substituted imidate 1a, for which
only low conversion was observed (entry 10). This result
indicates that the anion derived from the addition of α-alkyl
imidate 1a to 2a cannot extract the α-proton of 1a to complete
the catalytic cycle.
With the optimal reaction conditions in hand, we investigated
the scope of imidate and nitrosoarene substrates. Imidates
bearing α-alkyl substitutions such as ethyl, propyl, and benzyl
were all suitable coupling partners, giving the desired products
3b−d in good yields with excellent diastereoselectivities (Table
2, entries 2−4). α-Aryl-substituted imidates with electron-
neutral, electron-donating, or electron-withdrawing groups
attached to the aryl group underwent hydroxyamination in the
presence of a catalytic amount of base, providing α-(N-phenyl
hydroxyamino)arylacetimidates 3f−l with excellent asymmetric
induction (entries 6−12). The reaction of 1e was easily carried
out on a preparative scale using 0.1 equiv of NaHMDS, affording
product 3e in 76% yield without erosion of dr (entry 5).
Enantiomers of 3a and 3e were easily accessed by replacing (R)-
a
Reaction conditions: 1 (0.30 mmol), NaHMDS (0.36 mmol for
imidates 1a−d; 0.060 mmol for 1e−l), and 2 (0.39 mmol) in
anhydrous THF (3.0 mL) under argon at −78 °C, unless otherwise
b
c
noted. Isolated yield after silica gel chromatography. Determined by
d
1H NMR spectroscopy of the crude reaction mixture. (S)-Enantiomer
e
of N-tert-butanesulfinyl imidate was used. Refers to the N−O cleavage
product; for details, see the Supporting Information. Reaction on 1 g
scale using 0.10 equiv of NaHMDS.
f
tert-butanesulfinyl imidates 1a and 1e with the (S)-enantiomers
as starting material (entries 13 and 14).
Various nitrosoarenes could trap deprotoned 1a and 1e,
leading to the corresponding α-(N-aryl hydroxyamino) imidates
(entries 15−19 and 20−24). We failed in our attempts to extend
the reaction to nitrosoarenes containing two potential electro-
philic sites, such as 4-AcC6H4-NO and 4-MeO2CC6H4-NO;
these reactions led to unidentified mixtures. In the reactions to
produce α-hydroxyamination products 3c, 3g, 3q, and 3v, which
show poor stability at room temperature,15 the residues obtained
after common workup were immediately mixed with Zn/AcOH
to cleave the N−O bond and thereby afford the corresponding α-
arylamino products, which could be characterized (entries 3, 7,
19, and 24).
We crystallized the N−O bond cleavage product 4 derived
from 3e, via the reaction with Zn/AcOH, which gave quantitative
yield (Scheme 2). X-ray diffraction analysis of 4 showed that the
B
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Letter
addition of α-aryl substituted N-tert-butanesulfinyl imidates can
Scheme 2. Cleavage of the N−O Bond in α-Hydroxyamino N-
tBS Imidate and Further Manipulations
be realized by using a catalytic amount of base.18
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03835.
Experimental details, characterization data of all new
compounds (PDF)
X-ray crystal structure of compound 4 (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: clu@ms.xjb.ac.cn.
*E-mail: xuyj@ms.xjb.ac.cn.
ORCID
Chong-Dao Lu: 0000-0001-8968-0134
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (U1403301, 21372255, and 21572262),
the Recruitment Program of Global Experts (Xinjiang Program),
and the Director Foundation of XTIPC (2015RC014).
aminated α-carbon adopts the S-configuration,16 indicating that
the absolute configuration of 3e is (RS,2S). Configurations of
other hydroxyamination products were determined by analogy.
The crystal structure showed an E-configuration for the N-tBS
imidate, with the tBS and methoxy groups on opposite sides of
the CN bond. Because all N-tBS imidate derivatives of known
configuration are (E)-isomers,17 we infer that the hydroxyamino
imidates 3 adopt the same geometry.
To illustrate the synthetic utilities of this method, we
investigated further transformations of α-hydroxyamino imidate
3e (Scheme 2). Using 4 as a starting material, we transformed the
N-tBS imidate group into N-tBS α-primary and α-tertiary amine,
amide, and imine groups. We were able to obtain optically active
diamines 5 and 6, α-phenylamino amide 7, and α-phenylamino
N-tBS aldimine 8. Aldimine 8 is a suitable precursor for further
transformation into structurally diverse chiral 1,2-diamines.
The observed stereochemistry can be rationalized by
postulating si-face addition of (E)-aza-enolate 9 to aromatic
nitroso compounds via a well-known Ellman’s chelated chairlike
6/4-membered bicyclic transition state5b 10 to afford the
(RS,2S)-products (Scheme 3). The formation of (E)-aza-enolate
9 is favored, in which the R and bulky N-tBS groups are on
opposite sides of the CC bond to minimize steric hindrance.
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