Nucleophilic ring opening of aziridines with amines under catalyst- and solvent-free conditions

Article abstract of DOI:10.1039/c6gc03144g

The aza-addition of aziridines to obtain vicinal-diamines was achieved under catalyst- and solvent-free conditions for the first time. Various aryl, alkyl and meso-bicyclic aziridines with a Ts-protecting group were tolerated, and aromatic amine-nucleophi

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Nucleophilic Ring Opening of Aziridines with Amines under Catalyst-
and Solvent-free Conditions
Yi-Yong Huang,*a,b Zong-Chao Lv,a Xing Yang,a Zhao-Lei Wang,a Xiao-Xue Zou,a Zhen-Ni Zhaoa and
Fei Chenb
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The aza-addition of aziridines for vicinal-diamines was firstly
disclosed under catalyst- and solvent-free conditions. Various
aryl, alkyl and meso-bicyclic aziridines with a Ts-protecting
group were tolerated, and aromatic amine-nucleophiles
containing electron withdrawing and donating groups in the
phenyl ring were applied. The plausible reaction mechanism
involving hydrogen bonding and proton transfer was
proposed. The synthetic utility of one addition adduct to 4-
amino-1,2,3,4-tetrahydroisoquinoline derivative through
Pictet–Spengler reaction was realized.
H
H
H
N
H
N
O
CO2Et
S
O
N
H
OMe
AcHN
N
Ph
R
H
R = (CH2)4COOH
NH2 • H3PO4
TamifluTM
D-(+)-Biotin
(+)-CP-99,994
Fig. 1 Selected biologically active compounds containing vicinal
diamine moiety.
aziridines for adjacent diamines under neat condition.
At the outset of this study, easily available phenyl
aziridine 1a with a tosyl (Ts) Nꢀprotecting group was
synthesized. The mixture of 1a and aniline (1.1 equiv)
The occurrence of vicinal diamine motif is quite
common in natural and artificial organic compounds
exhibiting catalytical, biological and pharmacological
properties (Figure 1).1 Enantioenriched vicinal diamine
catalysts or ligands have found extensive application in
asymmetric catalysis,2 such as asymmetric (transfer)
hydrogenation, Michael, Mannich and aldol reactions.
Thus the exploration of highly efficient and selective
synthetic methodology to such type of molecules in a
racemic or chiral form remains extremely desirable,
especially in a green manner.3 Among the already
established protocols, ring opening reaction of nitrogen
nucleophiles and aziridine4 partners‒featuring a threeꢀ
membered strained ring‒represents an important way to
access vicinal diamines.5 According to the survey of
related studies, acidic (LOMOꢀlowering strategy) or
basic catalysis (HOMOꢀraising strategy) in solvent
media condition was usually taken up in such type of
transformations. In some cases, a large excess amount
of nitrogen nucleophiles were used to accelerate and
complete reactions. Environmental concerns prompted
us to seek for more userꢀfriendly and atomꢀeconomic
conditions of existing protocols.6 Recently, we have
disclosed an efficient azaꢀMichael addition of
fluorinated acrylic acid derivatives for βꢀfluoroalkylated
amino acids.7 Solventꢀfree synthesis condition based on
liquid nitrogen nucleophiles is the key to high level of
yield without the aid of any catalysts. To explore the
synthetic potential of this novel strategy, we herein set
up an unprecendented nonꢀcatalytic azaꢀaddition of
o
was stirred at 25 C, which was stopped after 4 h upon
solidification with providing the addition adduct in 53%
yield (Table 1, entry 1). The solidification speed was
increased by improving the reaction temperature to 35
oC, which made the reaction hardly completed (entry 2).
The yield wasn’t significantly enhanced until the
o
temperature rose to 50 C, with 0.8 h of homogeneous
stirring and 5.2 h of standing in solid state (83% yield,
entry 4). Furthermore, the use of 1.5 equivalent of
aniline was not beneficial to the yield (entry 5).
Swapping of the Nꢀprotecting group to Ms, Ns, Boc and
Cbz groups also couldn’t get superior result. Therefore,
the optimal condition‒as exhibited in entry 4‒was
established for the following studies.
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Table 1 Optimized conditiona
Table 2 Scope of aziridinesa
a
Unless otherwise noted, reactions were performed with aziridines (0.1
b
mmol) and aniline (0.11 mmol). Isolated yield through preparative thin
layer chromatography. Aziridines (0.1 mmol) and aniline (0.15 mmol)
c
were used.
The scope of various functionalized aryl and alkyl
aziridines with a Tsꢀprotecting group was carried out
under above optimized condition (Table 2). Comparing
with aziridine 1a, the introduce of a chloroꢀatom at the
orthoꢀposition of phenyl ring resulted in a slightly lower
yield (79%) (entry 2). In the case of metaꢀ and paraꢀ
chloroꢀsubstituted phenyl aziridines, higher yields of
91% and 87% were achieved respectively (entries 3ꢀ4).
Vicinal diamines 3ia and 3ja were accessed in excellent
yields by using paraꢀbromoꢀ and paraꢀfluoroꢀ
substituted phenyl aziridines (entries 5ꢀ6). Furthermore,
gemꢀPh,Meꢀdisubstituted phenyl aziridine 1k was tested
in 84% yield, resulting in the same reaction site of more
substituted carbon atom as above cases. However,
monoalkylꢀ and trialkylꢀsubstituted aziridines were
specifically attacked at the less substituted carbon atom
(92% and 64% yield, entries 8ꢀ9). Thus the
regioselectivities were highly governed by the
substituent structure of aziridines. Electronic effect
predominates when arylꢀsubstituents used, albeit steric
hindrance effect controls the regioselectivity with only
alkylꢀsubstituents. In addition, bicyclic mesoꢀaziridines
1n and 1o were also tolerated to provide the
corresponding adjacent diamines in excellent yields and
diastereoselectivities (entries 10ꢀ11).
a
Reactions were performed at 50 oC with aziridines (0.1 mmol) and
b
aniline (0.11 mmol).
chromatography, ND = not detected.
Isolated yield after preparative thin layer
Then we turned our attention on the effect of various
aromatic amineꢀnucleophiles on the ring opening of
aziridine 1a (Table 3). Upon using oꢀtoluidine 2b,
higher yield was obtained than the aniline case (entry 2
vs entry 1). Then several halogenꢀsubstituted anilines
were applied. oꢀChloroꢀ and mꢀfluoroanilines showed
less efficient than oꢀfluoroꢀ and pꢀfluoroanilines (entries
3ꢀ5, 7). Aniline with a strongly electronꢀwithdrawing
CF3 group at metaꢀposition showed wellꢀperformed
reactivity (entry 6), albeit the paraꢀCF3ꢀsubstituted case
(2h) led to much lower yield (entry 8). The highly steric
t
hindrance of Bu group at the paraꢀposition of aniline
resulted in good yield (entry 9). The use of disubstituted
aniline 2j generated the vicinal diamine product in good
yield (entry 10). It should be noted that the secondary
amine 2k also reacted well with 1a in excellent yield
(94%) (entry 11).
2
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Table 3 Scope of aminesa
Ts
N
RR'N
Ph
no catalyst
RR'NH
+
no solvent
NHTs
Ph
rac-1a
2
rac-3aa ak
Yield (%)b
R
R'
Entry
Amine
t (h)
Product
H
H
H
H
H
H
H
1
2
3
4
5
6
7
Ph
2a
2b
2c
2d
2e
2f
6
6
3aa
3ab
3ac
3ad
3ae
3af
83
88
82
94
85
95
91
o-Me-Ph
o-Cl-Ph
o-F-Ph
24
6
m-F-Ph
24
6
Scheme 1 Proposed reaction pathway.
m-CF3-Ph
p-F-Ph
2g
6
3ag
H
H
8
9
p-CF3-Ph
p-tBu-Ph
2h
2i
6
6
3ah
3ai
74
87
H
10
11
o,p-(OMe)2-Ph
2j
6
6
3aj
88
94
Scheme 2 Gramꢀscale synthesis of 3ak and synthetic application.
Ph
Me
2k
3ak
a
Reactions were performed at 50 oC with aziridines (0.1 mmol) and
b
In summary, we have discovered that the reaction of
Tsꢀprotected aziridines and amines proceeded well
under neat condition without the aid of any catalyst. A
wide variety of adjacent amines could be available (up
to 95% yield) via this green process. A short synthesis
of an important 4ꢀaminoꢀ1,2,3,4ꢀtetrahydroisoquinoline
scaffold further highlight the synthetic utility. It should
be noted that <99% level of isolated yields in all azaꢀ
additions mainly resulted from the incomplete
conversion of staring materials–could be recovered–for
solidification, instead of chemoꢀ, regioꢀ or
diastereoselectivities. However, the presence of metal
Lewisꢀcatalysts in such type of reactions5f,5h,5i usually
resulted in regioisomers. We believe this catalystꢀ and
solventꢀfree strategy may be applied in more and more
protocols in the future.
aniline (0.11 mmol).
chromatography.
Isolated yield through preparative thin layer
The postulated reaction mechanism of aromatic
aziridines and amines was illustrated in Scheme 1.
Initially, two reaction components are combined through
intermolecular hydrogen bonding, which makes the two
reaction sites in close proximity. Control experiment of
using substrates 1a and 2a along with one equivalent of
MeOH additive revealed a decreasing reaction rate (45%
yield after 6 h at 50 oC). It indicates the weak hydrogen
bond could be destroyed by MeOH, thus retarded the
reaction. Thereafter, the azaꢀaddition proceeds in an
intramolecularꢀlike manner to provide dipolar
intermediate II, which immediately undergoes protonꢀ
transfer reaction to generate product 3.
In order to demonstrate the practicalities and
synthetic application of such solventꢀ and catalystꢀfree
azaꢀaddition, gramꢀscale reaction of components 1a and
2k was commenced at first. Compound racꢀ3ak was
furnished in the same level of yield as that of small
scale reaction, which facilitated the Pictet–Spengler
Acknowledgements
We gratefully thank the financial support of this investigation by
the National Natural Science Foundation of China (Nos.
21303128, 21573169), and the Fundamental Research Funds for
the Central Universities (WUT: 2016IB007, 2016ꢀYBꢀ007).
reaction with polyformaldehyde8 to yield
4ꢀaminoꢀ
1,2,3,4ꢀtetrahydroisoquinoline9 derivative 4 of potential
pharmacological interest (Scheme 2).10
Notes
a Department of Chemistry, School of Chemistry, Chemical Engineering
and Life Science, Wuhan University of Technology, Wuhan 430070,
China; Eꢀmail: huangyy@whut.edu.cn
b Beijing National Laboratory for Molecular Sciences (BNLMS), Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
† Electronic Supplementary Information (ESI) available: General
experimental procedures, NMR and HRMS data of all new compounds
are included. See DOI: 10.1039/b000000x/
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Aza-addition of aziridines under catalyst- and solvent-free conditions were performed
to provide access a wide array of vicinal diamines in up to 95% yield, thus facilitated
the scale-up synthesis of 4-amino-1,2,3,4-tetrahydroisoquinoline derivative.