A Route to Polysubstituted Aziridines from Carbenes and Imines through a Nondiazo Approach

Article abstract of DOI:10.1021/acs.orglett.6b02429

An efficient method for the synthesis of polysubstituted aziridines utilizing enynones and imines is described. This transformation is achieved through the reaction of imines with donor/donor carbene intermediates, which were generated in situ from the cyclization of enynones. Furthermore, the resulted aziridines were good 1,3-dipoles, which could be efficiently trapped by dipolarophiles to give five-membered heterocycles. The obvious advantages of wide substrate scopes, mild reaction conditions, and high atom efficiency make this system highly appealing for construction of polysubstituted aziridines, 2,5-dihydropyroles, and 1,2,4-triazolidines.

Full text of DOI:10.1021/acs.orglett.6b02429

Letter
pubs.acs.org/OrgLett
A Route to Polysubstituted Aziridines from Carbenes and Imines
through a Nondiazo Approach
Hejiang Luo, Kai Chen, Huanfeng Jiang, and Shifa Zhu*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
*
S Supporting Information
ABSTRACT: An efficient method for the synthesis of polysubstituted
aziridines utilizing enynones and imines is described. This transformation is
achieved through the reaction of imines with donor/donor carbene
intermediates, which were generated in situ from the cyclization of
enynones. Furthermore, the resulted aziridines were good 1,3-dipoles, which
could be efficiently trapped by dipolarophiles to give five-membered
heterocycles. The obvious advantages of wide substrate scopes, mild reaction
conditions, and high atom efficiency make this system highly appealing for
construction of polysubstituted aziridines, 2,5-dihydropyroles, and 1,2,4-
triazolidines.
ziridines are useful synthetic intermediates in organic
synthesis and are structural units of many natural products
Scheme 1. Carbene-Transfer Reaction with Enynone as
Carbene Source
A
1
2
and drugs. Various synthetic methods of aziridines, including
3
several asymmetric versions, have been reported in the past
decades. Synthetic methodologies for the preparation of
4
aziridines include nitrene addition to olefins, carbene and
ylide addition to imines, Lewis acid catalyzed diazo compounds
4f
addition to imines, and cyclization of 1,2-amino alcohols, 1,2-
4
g
4h
amino halides, and 1,2-azido alcohols. The addition of
metal−carbenoids to imines or Lewis acid catalyzed addition of
diazo compounds to imines are most attractive pathways
because of their mild reaction conditions, good selectivities, and
5
well-established catalytic systems. However, the substrates
containing the highly energetic diazo moiety are often unstable,
explosive, and toxic, particularly for those donor or donor/
donor diazo compounds. These disadvantages severely limit the
6
application of these methodologies.
Recently, enynal/enynone has emerged as one of the most
reliable and safe donor or donor/donor−carbene precusors,
which have been widely applied in classic carbene-transfer
reactions such as cyclopropanation and C−H/X−H insertion
7
,8
reactions. As part of our continuous efforts to develop new
8e,f,s,9
tandem reactions based on enynal/enynone,
we have
successfully applied enynal/enynone as the donor or donor/
donor carbene precursors for the carbene-transfer reactions.
For example, we developed a highly efficient NHC-AuCl/
Selectfluor-catalyzed carbene-transfer reaction based on eny-
nal/enynone chemistry with turnover numbers (TONs) up to
addition of donor/donor metal−carbenoids to imines based
on a diazo approach or Lewis acid catalyzed addition of donor/
donor diazo compounds to imines due to obvious safety
concerns.
8
s
Herein, we report the first aziridination from the reaction of
enynones and imines. Initially, enynone 1a and imine 2a were
chosen as the model substrates for this investigation. As shown
in Table 1, the reactions were conducted in CH Cl at 60 °C.
9
90000. Furthermore, we also developed the first enantiose-
lective intramolecular C−H insertion of donor and donor/
donor carbenes by an enynal/enynone approach, with ee values
8e
2
2
up to 99% (Scheme 1). Inspired and encouraged by the above
results, we envisaged that this method might be further
extended to the synthesis of polysubstituted aziridines, which
would provide an attractive alternative to the traditional
Received: August 14, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
catalyze this reaction either (Table 1, entry 5). Gratifyingly, the
desired aziridine 3a could be successfully obtained in 76% and
8
5% yields when Rh (OAc) and Rh (OPiv) were applied as
2 4 2 4
the catalysts (Table 1, entries 6 and 7). The reaction yield
remained unchanged when the reaction was conducted at room
temperature (Table 1, entry 8). Other solvents, such as DCE,
toluene, and THF, gave inferior results (Table 1, entries 9−11).
Further control experiments indicated that the reaction did not
occur without catalyst (Table 1, entry 12). It is noted that
excellent diastereoselectivities of aziridine 3a (dr >20:1) were
observed for the rhodium-catalyzed conditions in Table 1,
which could be attributed to the π−π stacking interactions of
two cis-phenyl groups.
entry
cat. (mol %)
temp (°C)
solvent
CH Cl
3a (%)
1
2
3
4
5
6
7
8
9
AgNTf (5)
60
60
60
60
60
60
60
rt
ND
ND
ND
ND
ND
76
2
2
2
Ph PAuNTf (5)
CH Cl
3
2
2
2
2
2
2
2
2
Cu(OTf) (5)
CH Cl
2
2
CuBr (5)
CH Cl
2
ZnCl (5)
CH Cl
2
2
Rh (OAc) (1)
CH Cl
With the optimized reaction conditions (Table 1, entry 8) in
hand, the substrate scope was then examined (Scheme 2). First,
the reaction could be conducted on a gram scale and gave the
product 3a in 88% yield. Second, this catalytic system could be
successfully applied to a variety of enynones 1 and imines 2 as
well. For example, in addition to enynone 1a, various enynone
2
4
2
Rh (OPiv) (1)
CH Cl
85
2
4
2
b
Rh (OPiv) (1)
CH Cl
86
2
4
2
2
Rh (OPiv) (1)
rt
DCE
72
2
4
1
1
1
0
1
2
Rh (OPiv) (1)
rt
toluene
THF
70
2
4
Rh (OPiv) (1)
rt
36
2
4
1
rt
CH Cl
ND
derivatives tethered with aryl groups (R = aryl) could be
2
2
a
effectively reacted with imine 2a, giving the desired aziridines
3a−h in 68−88% yields. The reaction was not sensitive to the
electronic properties of enynones 1, the enynones with both
electron-withdrawing and -donating substituents at the aryl
1
a (0.2 mmol), 2a (0.4 mmol), [1a] = 0.2 M. The yield was
1
determined by H NMR using CH NO as an internal standard. dr
value was estimated by H NMR. Isolated yield.
3
2
1
b
1
Different transition metals were tested for this transformation.
The coinage metal salts, which were typically good catalysts for
enynones,
desired product 3a was detected (Table 1, entries 1−4). ZnCl ,
another important catalyst in the literature,
groups of R could be utilized as good substrates for this
1
reaction. Alkyl enynone (R = n-hexyl) transferred to the
8
h−m
were ineffective for this transformation; no
corresponding aziridine 3i in 62% yield. The reactions for
propionyl-, benzoyl-, and ethoxycarbonyl-substituted enynones
proceeded equally well, leading to the desired products 3j−l in
2
8b−d
could not
a
Scheme 2. Substrate Scope of Aziridination
a
b
1
c
d
Rh (OPiv) (1 mol %), 1 (0.2 mmol), 2 (0.4 mmol), [1] = 0.2 M, 3−12 h, isolated yield. Estimated by HNMR. 1a (5 mmol). trans/cis = 5:1.
2
4
e
f
g
trans/cis = 3:1. trans/cis = 10:1. trans/cis = 4:1.
B
DOI: 10.1021/acs.orglett.6b02429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
7−82% yields. In addition to the enynones, we also
diethyl azodicarboxylate in the presence of 1 mol % of
Rh (OPiv) (Scheme 4).
investigated different imines. As shown in Scheme 2, the
reactions were not sensitive to the electronic and steric
properties of the imines. For example, the imines with different
2
4
a
Scheme 4. Three-Component Reaction
4
5
electronic properties and steric hindrance on both R and R
groups could serve as good substrates for this transformation,
furnishing the desired aziridines 3m−ab in 64−90% yields.
Steric bulky imines could be aziridinated smoothly, leading to
the desired products 3t, 3u, and 3ab in 74−85% yields.
Furthermore, the imine derived from furan-2-carbaldehyde was
also an efficient substrate, affording the aziridine 3v in 83%
yield. The imine from aliphatic amine was not an effective
substrate for this reaction, and only a trace of the desired
product 3ac could be detected. The structure and stereo-
chemistry of the product were confirmed by the X-ray
diffraction analysis of compound 3x (see the Supporting
Information).
a
The reaction was conducted in a sealed tube.
Interestingly, the relative stereochemistry has been reversed
during the cycloaddition process. Two phenyl groups situated
cis to each other in azirindines 3a and 3g but trans in the
adducts 4a−d (Scheme 3). These results indicated that the [3 +
2]-cycloaddition of the aziridine 3 and dipolarophile is a
stepwise process.
With aziridines 3 substituted with three different aryl groups
in hand, we were very curious about the reactivity of these
electron-rich aziridines. Electron-rich aziridines were often
regarded as effective precursors of azomethine ylides, which are
With the above results, a plausible mechanism was then
8s
proposed (Scheme 5).
10
good 1,3-dipoles in [3 + 2]-cycloadditions. Therefore, several
electron-deficient dipolarophiles, dimethyl acetylenedicarbox-
ylate, diethyl acetylenedicarboxylate, and diethyl azodicarbox-
ylate were then tested for the [3 + 2]-cycloadditions. As shown
in Scheme 3, simply refluxing the solution of aziridines 3 and
Scheme 5. Proposed Reaction Mechanism
Scheme 3. Chemical Transformation of Aziridines 3
Taking aziridine 3a, for example, the coordination of the
triple bond of the enynone 1a to rhodium catalyst enhanced the
electrophilicity of the alkyne, and subsequent intramolecular
nucleophilic attack of the carbonyl oxygen atom to the electron-
deficient alkyne would form the intermediate B, which was in
equilibrium with the carbene intermediate C. In the presence of
imine 2a, the carbene intermediate was then trapped to form
the aziridine 3a. The electron-rich aziridine 3a was a good
a
The stereochemistry was determined by X-ray diffraction analysis.
The stereochemistry was determined by NOE.
b
dipolarophiles smoothly furnished the desired 2,5-dihydropyr-
oles and 1,2,4-triazolidines in good to excellent yields (4a−d,
7
10
precursor of azomethine ylide D or 1,3-dipole E, which could
further react with the electron-deficient dipolarophile, such as
DMAD, to produce the desired adduct 4a.
2−95%). The furan ring of aziridine 3a could be used as the
π-component to react with benzyne through the [4 + 2]-
4
cycloaddition reaction, giving the product 4e in 55% yield. The
structure and stereochemistry of 2,5-dihydropyrole and 1,2,4-
triazolidine were further confirmed by the X-ray diffraction
analysis of compounds 4b and 4d (see the Supporting
Information).
Furthermore, 1,2,4-triazolidine 4c could also be obtained in a
one-pot manner from the reaction of enynone 1a, imine 2a, and
In summary, we have developed an efficient method for the
synthesis of polysubstituted aziridines from enynones and
imines. This transformation is achieved through a reaction of
imines with donor/donor carbene intermediates, which were
generated in situ from the cyclization of enynones.
Furthermore, the resulting aziridines were good 1,3-dipoles
which could be efficiently trapped by electron-deficient
C
DOI: 10.1021/acs.orglett.6b02429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dipolarophiles to give five-membered heterocycles. The obvious
advantages of wide substrate scopes, mild reaction conditions,
and high stereoselectivity and atom efficiency make this
reaction highly appealing for construction of polysubstituted
aziridines, 2,5-dihydropyroles, and 1,2,4-triazolidines.
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ASSOCIATED CONTENT
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Supporting Information
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ACS Publications website at DOI: 10.1021/acs.or-
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Typical experimental procedure and characterization for
all products (PDF)
Crystallographic data for 3x (CIF)
Crystallographic data for 4b (CIF)
Crystallographic data for 4d (CIF)
4
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AUTHOR INFORMATION
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(
2
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Corresponding Author
*E-mail: zhusf@scut.edu.cn.
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ACKNOWLEDGMENTS
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J.; Riesgo, L.; Vicente, R.; Lop
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We are grateful to Ministry of Science and Technology of the
People’s Republic of China (2016YFA0602900), the NSFC
2
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ez, L.
́
(
(
21372086, 21422204, and 21672071), Guangdong NSF
2014A030313229, 2016A030310433), China Postdoctoral
1
Science Foundation (2015M582378, 2016T90777), and the
Fundamental Research Funds for the Central Universities,
SCUT.
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DOI: 10.1021/acs.orglett.6b02429
Org. Lett. XXXX, XXX, XXX−XXX