Iron-Catalyzed Aminomethyloxygenative Cyclization of Hydroxy-α-diazoesters with N,O-Aminals

Article abstract of DOI:10.1002/cjoc.201900492

A new and efficient cyclization reaction has been developed to synthesize cyclic α,α-disubstituted β-amino esters via iron-catalyzed intramolecular aminomethyloxygenative cyclization of diazo compounds with N,O-aminal under mild reaction conditions. A bro

Full text of DOI:10.1002/cjoc.201900492

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Iron-Catalyzed Aminomethyloxygenative Cyclization of Hydroxy-α-diazoesters
with N,O-aminals
Authors: Suchen Zou, Tianze Zhang, Siyuan Wang, and Hanmin Huang*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.201900492.
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Iron-Catalyzed
Aminomethyloxygenative
Cyclization
of
Hydroxy-α-diazoesters with N,O-aminals
Suchen Zou,a Tianze Zhang,a Siyuan Wang,a and Hanmin Huang*,a,b
aHefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis, University of
Science and Technology of China, Chinese Academy of Sciences, Hefei, 230026, P. R. China.
bState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, P. R. China.
Cite this paper: Chin. J. Chem.2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion: A new and efficient cyclization reaction has been developed to synthesize cyclic α,α-disubstituted
β-amino esters via iron-catalyzed intramolecular aminomethyloxygenative cyclization of diazo Compounds with N,O-aminal under mild reaction
conditions. A broad range of hydroxy-α-diazoesters with different substituents and various N,O-aminals were compatible with this protocol, affording the
corresponding α,α-disubstituted β-amino esters bearing with a five- to eight-membered oxacycle in good yields.
α-Diazocarbonyl compounds are quite valuable precursors in
synthetic organic chemistry due to their versatile reactivity and
Background and Originality Content
α,α-Disubstituted β-amino acids are key motifs found in
remarkable synthetic values. They have been utilized in a broad
numerous natural products and biologically active molecules,1 and
range of transformations such as metal-catalyzed X-H (X = N, O, S,
they are also key building blocks in organic synthesis.2 More
Si, et al) bond insertions, cyclopropanation, ylide formation, and
specifically, cyclic α,α-disubstituted β-amino acids are interesting
compounds due to their unique biological activities and antiviral
properties. For example, the chiral dysibetaine and epidysibetaine
have been isolated from the aqueous extract of the marine
sponge Dysidea herbacea collected from Yap, Micronesia,3 the
proline-derived spiro-β-lactam III serves as an efficient β-turn
nucleator,4 CCR5 antagonists display potent anti-HIV activity,5
whereas Sch58053 exhibits cholesterol absorption inhibiting
activity (Figure 1).6 On the other hand, cyclic α,α-disubstituted
β-amino acids can be utilized as synthetic precursors for
spiro-β-lactams.7 However, despite the substantial interest in
these amino acids and their applications in drug design, only a few
synthetic approaches have been developed, with the majority of
them being of limited scope. Therefore, the development of more
general and straightforward synthetic methods toward these
compounds is in high demand.
1,2-migration reactions.8 Among these reactions, strategies for
constructing amino acids have drawn increasing attention by using
α-diazo esters. For instance, transition-metal-catalyzed insertion
of metal carbenes or carbenoids generated in situ from
α-diazoesters into N-H bonds has been developed to the
preparation
of
α-amino
acid
derivatives,8d-e,g-j
and
transition-metal-catalyzed multicomponent reactions involving
diazo compounds with alcohols and imines (iminiums) were
documented for the construction of α-hydroxy-β-amino esters.9 In
2015, we developed a synthetic methodology for the efficient
construction of a,β-diamino acid esters bearing a quaternary
carbon-center by palladium-catalyzed formal insertion of
carbenoids into aminals via C-N bond activation.10 More recently,
we and several other groups have demonstrated that N,O-aminals
are also valuable aminomethylation reagents to react with diazo
compounds to deliver the α-hydroxy-β-amino esters (Scheme
1-1).11 These results inspired us to consider whether the
construction of oxacycles- α, α-disubstituted β-amino esters can
be achieved by reacting hydroxyl tethered α-diazoesters with
N,O-aminals under suitable conditions. In continuation with our
ongoing interest in the aminal chemistry,10,11a,12 we herein report
an iron-catalyzed intramolecular aminomethyloxygenative
cyclization reaction between hydroxyl-tethered α-diazoesters and
N,O-aminals, which provides a new and rapid approach to
oxacycle-containing α,α-disubstituted β-amino esters (Scheme
1-2).
OH
H
OH
Me3N
O2C
N
O2C
NMe3
O
N
O
O
N
O
N
HN
H
H
t-BuO
O
-lactam III
β
(R,R)-dysibetaine (S,R)-epidysibetaine
F
proline-derived spiro-
Cl
N
N
OH
H
N
HO
N
O
O
N
O
OH
F
CCR5
Sch 58053
Antagonist
Figure 1. Biologically active molecules containing cyclic α,α-disubstituted
β-amino acid units
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10.1002/cjoc.201900492
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First author et al.
Report
work:
Previous
formal insertion of carbenoids into
NR2
-aminals
N,O
7
8
AgOTf
Fe(OTf)3
Fe(OTf)2
Fe(acac)3
FeCl3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
14
71
72
41
70
R'
O
N2
80
80
80
80
Et
CO2
M
[
]
+
(1)
(2)
R1
=
NR2
Et
CO2
OR'
Pd, Cu)
R1
9
(M
10
11
work:
This
with
-aminals
N,O
aminomethyloxygenative cyclization
R2
O
R2 R3
R1
NR2
CO2
NR2
mol%)
Fe(OTf)2 (5
R1
+
CO2
HO
12
13
14
15
16
17
18
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
-
DCM
PhCN
80
80
80
60
40
25
25
67
68
60
75
76
76
<5
CH3CN
1-4)
n
n
OMe
R3
N2
1
2
3
(n=
DMF
• alcohol
• mild reaction conditions
• five to rings
&
phenol hydroxyl
CH3CN
CH3CN
CH3CN
CH3CN
•
metal catalyst
inexpensive
eight-membered
Scheme
1
Catalytic
aminomethyloxygenative
cyclization
of
hydroxy-α-diazoesters with N,O-aminals.
a
Reaction condition: 1a (0.45 mmol), 2a (0.3 mmol), catalyst (0.015
Results and Discussion
mmol), solvent (1.0 mL), 12 h. b Isolated yield.
On the basis of our previous results, we initially
commenced our study by investigating the reaction between
With the optimal reaction conditions identified, the generality
of the iron-catalyzed aminomethyloxygenative of diazo
compounds was investigated. The scope of various N,O-aminals 2
was explored firstly with benzyl 2-diazo-5-hydroxypentanoate 1a
at 25 °C by using Fe(OTf)2 as the catalyst. As illustrated in Table 2,
The reaction of N,O-aminals, derived from benzylamines bearing a
variety of electron-withdrawing (F) and -donating groups (Me,
OMe), proceeded well to deliver the products in the range of
63-74% yields (3aa-3ad). N,O-Aminals derived from CH3OH and
simple aliphatic amines, such as diallylamine, dipropylamine,
dibutylamine and dicyclohexylamine could react smoothly with 1a
to give the corresponding products in moderate yields (3ae-3ah).
At the same time, N,O-aminals prepared from cyclic amines were
also applicable as coupling partners, giving the corresponding
products (3ah and 3ai) in good yields.
benzyl
2-diazo-5-hydroxypentanoate
(1a)
and
N,N-dibenzyl-1-methoxymethanamine (2a) in CH3CN at 80 oC with
5 mol% of palladium catalyst. However, only moderate yields
were obtained (Table 1, entries 1 and 2). To our delight, when
Zn(OTf)2 was introduced into the reaction system, the
aminomethyloxygenative cyclization product 3aa was obtained in
67% isolated yield (Table 1, entry 3). Inspired by this result, we
then investigated a series of Lewis acids. When Fe(OTf)2 was
introduced into the reaction system, the reaction proceeded well
to give 3aa in 72% isolated yield while other Lewis acids didn’t
give better results (Table 1, entries 4-11). To maximize the
efficiency of this reaction, a variety of solvents were screened and
found that CH3CN was the best solvent for the present reaction
(Table 1, entries 12-14). We then examined the effect of
temperature and found that the reaction could proceed smoothly
at room temperature to give the desired product in 76% isolated
yield (Table 1, entry 17). As anticipated, control reactions
demonstrated that only trace amount of the desired product 3aa
was obtained in the absence of catalyst (Table 1, entry 18).
Table 1 Optimization of Reaction Conditionsa
NBn2
O
Bn
CO2
Catalyst mol%)
(5
Bn
CO2
+
HO
NBn2
mL)
CH CN
(1.0
3
OMe
N2
12 h
1a
2a
3aa
Entry
Catalyst
Solvent
T (oC)
Yield (%)b
1
2
3
4
5
6
Pd(XantPhos)(CH3CN)2(OTf)2
Pd(dppe)(CH3CN)2(SbF6)2
Zn(OTf)2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
80
80
80
80
80
26
42
67
70
66
69
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
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Chin. J. Chem. 2019,37, XXX－XXX
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Running title
Chin. J. Chem.
31% yield (3ka) by using this method under slightly modified
reaction conditions.
Table 2 Substrate scope of N,O-aminalsa
Table 3 Substrate scope of α-diazoestersa
NR2
O
Bn
CO2
mol%)
Bn
CO2
Fe(OTf)2 (5
CH CN
HO
+
NR2
N2
(1.0 mL),
3
OMe
2
R2
R2 R3
25 o 12 h
CO2
NR2
R1
O
NR2
mol%)
mL)
C,
Fe(OTf)2 (5
CH CN
1
3
+
R1
CO2
HO
n
OMe
(1.0
3
n
Entry
Yield
(%)
3
R
R3
N2
1-4)
(n=
1
2
3
H
C6 5CH2
1
2
3aa
76
74
R1
O
CO2
NBn2
O
O
4-MeC6H4CH2
3ab
Et
CO2
CO2Et
NBn2
NBn2
,
3aa R1
H
4-MeOC6H
4CH2
=
3
4
3ac
3ad
63
71
C6 5CH
2 (76%)
3 (71%)
,
3ba R1
(49%)b
=
3ea
CH
,
,
3fa
(59%)
3 (67%)
3ca R1
2-FC6H4CH2
=
CH2CH
C(CH3)3 (75%)b
,
3da R1
=
,
CH2CHCH2
5
6
7
3ae
3af
37
55
48
O
Bn
CO2
O
Et
CO2
CH2CH2CH3
CH2CH2CH2CH3
NR2
NBn2
,
2 (51%)b
=
3ag
R
H
C6 5CH
3ga
2 (60%)b
=
R
H
3-ClC6 4CH
,
3gj
,
(59%)b
3ha
(59%)b
(57%)b
=
R
H
4-ClC6 4CH2
,
-CH(CH2 5
)
3ah
3ai
50
65
3gk
8
9
X-ray structure of
O
3gk
=
R
4-BrC6H
4CH2
,
3gl
-
-CH2CH2OCH2CH2
O
O
Et
CO2
Et
CO2
Et
CO2
Ts
N
NBn2
NBn2
N
NBn2
Ts
b
b
b,c
3ia
3ka
,
(31%)
,
3ja
(44%)
,(50%)
a Reaction condition: 1 (0.45 mmol), 2 (0.3 mmol), Fe(OTf)2 (0.015 mmol, 5
mol%), CH3CN (1.0 mL), 25 oC, 12 h. Isolated yield.
a Reaction condition: 1 (0.45 mmol), 2 (0.3 mmol), Fe(OTf)2 (0.015 mmol, 5
mol%), CH3CN (1.0 mL), 25 C, 12 h. Isolated yield. b 80 oC. c Fe(OTf)2 (0.03
mmol, 10 mol%), CH3CN (5.0 mL), 12 h.
o
After investigating the generality of N,O-aminals, various
hydroxyl-tethered α-diazoesters 1 were employed in the reaction
with N,N-dibenzyl-1-methoxymethanamine 2a. As shown in Table
3, the substrates with 5-hydroxy chains (1a-1e) afforded the
corresponding β-amino esters with five-membered rings in good
yields (3aa-3ea). Substrate 1d with a tert-butyl ester group
afforded the desired product in 75% yield by increasing the
We further evaluated the utility of this reaction by performing
a large-scale experiment (Scheme 2). Under the standard reaction
conditions, the desired product 3aa could be obtained in gram
scale (2.4 g) with 72% isolated yield. The scalability and
robustness of this transformation indicate its potential application
in the preparation of fine chemicals. Then we carried out several
transformations of cyclization product 3aa (Scheme 2). Reduction
of the ester group with LiAlH4 gave the product 4 in 96% isolated
yield.13 Hydrolysis of the ester with LiOH as the base gave
carboxylic acid 5 in good yield. In addition, one benzyl group
contained in 3aa could be selectively removed to give
benzyl-2-((benzylamino)methyl)tetrahydrofuran-2-carboxylate 6 in
84% yield in the presence of ClCO2CHClCH3.15 Cyclization of
o
temperature to 80 C. It is worth mentioning that α-diazoesters
attached to a phenolic hydroxyl group was applicable to this
reaction (3ea). To our delight, the catalyzed reaction was also
suitable for the aminomethyloxygenative cyclization of benzyl
2-diazo-6-hydroxyhexanoate, which yielded the corresponding
oxacycle-containing α,α-disubstituted β-amino esters with
o
six-membered rings under 80 C in the presence of 5 mol% of
catalyst (3fa-3ha, 3gj-3gl). N,O-aminals, derived from
benzylamines bearing electron-withdrawing (Cl, Br) group were
helpful for increasing the yield of the reaction (3gj-3gl). Moreover,
A benzo group in the chain of the substrate also had a positive
effect on the reactivity (3ha). The solid state structure of 3gk was
product
6
with
i-PrMgBr
gave
the
spiro-lactam
2-benzyl-5-oxa-2-azaspiro[3.4]octan-1-one 7 in 94% yield.11a
Scheme 2 Reaction scale-up and functional group transformationa
CO2Bn
O
O
NBn2
CO2Bn
a
unambiguously
determined
by
single-crystal
X-ray
standard condition
OH
NBn2
+
NBn2
crystallographic analysis.14 Motivated by the successful
construction of cyclic α,α-disubstituted β-amino esters with five-
and six-membered rings, we sought to extend the present
reaction to more challenging cycle with large ring sizes. As
expected, when 7-hydroxy-2-diazoesters (1i and 1j) were used as
substrates, the desired products with a seven-membered ring
were isolated in moderate yields. Importantly, the
eight-membered ring product was also successfully produced in
N2
OMe
HO
3aa
2.4g, 72%
4
2a
1a
yield
96%
yield
O
O
O
O
CO2
H
c
CO2Bn
d
b
NBn
NBn2
NHBn
7
6
5
94%
84%
yield
89%
yield
yield
Chin. J. Chem. 2019,37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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This article is protected by copyright. All rights reserved.

First author et al.
Report
with EtOAc/hexane (1/30 – 1/10) to afford the desired product
3aa.
o
a Reaction condition: a. LiAlH4 (1.0 eq.), THF, 0 C, 1 h; b. LiOH (5.0 eq.),
o
MeOH/H2O/THF (5:1:1), rt, 12 h; c. (i) ClCO2CHClCH3 (6.0 eq.), DCE, 80 C,
12 h, (ii) MeOH, 80 oC, 6 h; d. i-PrMgBr (2.0 eq.), rt, 12 h.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2019xxxxx.
In accordance with precedent studies16 and our experimental
results, a plausible mechanism for the formation of 3aa is
proposed (Scheme 3). In the first stage, the iminium I could be
generated from N,O-aminal 2a under the assistant of Fe(OTf)2.
Upon trapping with the nucleophile dizao II, the procarbonium ion
intermediate III could be generated from iminium I. Subsequently,
the intermediate III may undergo intramolecular oxygenative
cyclization to produce the desired oxacycle-containing
α,α-disubstituted β-amino esters.
Acknowledgement
This research was supported by the National Natural Science
Foundation of China (Nos. 21925111, 21672199, 21790333, and
21702197) and the Fundamental Research Funds for the Central
Universities (No. WK2060190086).
References
Scheme 3. Plausible reaction pathway
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MeOH
NBn2
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CO2
NBn2
OMe
OH
MeOFeOTf
Bn
CO2
2 OTf-
N+Bn
I
NBn2
N2
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III
OH
OH
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Conclusions
In summary, we have developed a new and efficient protocol
for the synthesis of oxacycle-containing α,α-disubstituted β-amino
esters via iron-catalyzed aminomethyloxygenative of diazo
compounds with N,O-aminals under mild reaction conditions. The
reaction proceeded well to furnish the desired products with good
functional-group compatibility, which provided a rapid and
reliable approach to unnatural oxacycle-containing β-amino esters
with five to eight-membered rings. Further studies to apply this
strategy are in progress in our laboratory.
Experimental
The Fe(OTf)2 (5.3 mg, 0.025 mmol) was added to a 25 mL
flame-dried Young-type tube in the glove box. Then
N,N-dibenzyl-1-methoxymethanaminel 2a (0.5 mmol), CH3CN (1.0
mL), benzyl 2-diazo-5-hydroxypentanoate 1a (114.0 mg, 1.0 mmol)
were added under argon atmosphere. The mixture was stirred at
o
25 C for 12 hours. The solvent was removed under reduced
pressure after the reaction finished. The reaction mixture was
purified by flash column chromatography on silica gel and eluted
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A New α,α-Disubstituted α-Amino Acid Derivative from the Marine
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019,37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019,37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
R2
R2 R3
R1
O
NR2
CO2
Title Iron-Catalyzed Aminomethyloxygenative
Cyclization of Hydroxy-α-diazoesters with
N,O-aminals
Fe(OTf)2
CH3CN
+
R1
CO2
NR2
HO
n
n
OMe
R3
N2
1
2
3
1-4)
(n=
• alcohol
• mild reaction conditions
• five to rings
&
phenol hydroxyl
•
metal catalyst
inexpensive
eight-membered
A new and efficient cyclization reaction has been developed to synthesize cyclic α,α-disubstituted
β-amino esters via iron-catalyzed intramolecular aminomethyloxygenative cyclization of diazo
Compounds with N,O-aminal under mild reaction conditions.
A
broad range of
hydroxy-α-diazoesters with different substituents and various N,O-aminals were compatible with
this protocol, affording the corresponding α,α-disubstituted β-amino esters bearing with a five- to
eight-membered oxacycle in good yields.
Suchen Zou,a Tianze Zhang,a Siyuan Wang,a and
Hanmin Huang*,a,b
Chin. J. Chem. 2019,37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.