Regioselective Three-Component Synthesis of Vicinal Diamines via 1,2-Diamination of Styrenes

Article abstract of DOI:10.1021/acs.orglett.1c00898

The vicinal diamine motif plays a significant role in natural products, drug design, and organic synthesis, and development of synthetic methods for the synthesis of diamines is a long-standing interest. Herein, we report a regioselective intermolecular three-component vicinal diamination of styrenes with acetonitrile and azodicarboxylates. The diamination products can be produced in moderate to excellent yields via the Ritter reaction. Synthetic applications and theoretical studies of this reaction have been conducted.

Full text of DOI:10.1021/acs.orglett.1c00898

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Letter
Regioselective Three-Component Synthesis of Vicinal Diamines via
1,2-Diamination of Styrenes
Jie Cao, Daqi Lv, Fei Yu, Mong-Feng Chiou, Yajun Li, and Hongli Bao*
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ABSTRACT: The vicinal diamine motif plays a significant role in natural products,
drug design, and organic synthesis, and development of synthetic methods for the
synthesis of diamines is a long-standing interest. Herein, we report a regioselective
intermolecular three-component vicinal diamination of styrenes with acetonitrile and
azodicarboxylates. The diamination products can be produced in moderate to
excellent yields via the Ritter reaction. Synthetic applications and theoretical studies
of this reaction have been conducted.
Scheme 1. Three-Component Vicinal Diamination of
Alkenes
he vicinal diamine motif is widely prevalent in many
natural products and a large number of bioactive
T
compounds with specific biological activities.1 The motif
provides a valuable platform for organic synthesis and catalyst
design.2 Consequently, facile synthesis of vicinal diamines has
attracted an increasing amount of attention from the chemical
community.3 Although significant advances have been made,
development of direct vicinal diamination reactions with
readily available alkenes is a challenge and a long-standing
interest in organic synthesis.
In recent decades, taking advantage of the abundant supply
of alkenes, direct vicinal diamination of alkenes has been
recognized as a rapid and straightforward method for
producing structurally diverse vicinal diamines,3b−d and to
date, much effort has been expended in this promising research
area. For example, cyclic vicinal diamines can be accessed
through intramolecular vicinal diamination of an inherent C
C bond under metal-free conditions4 or in the presence of a
metal catalyst.5 Two-component vicinal diamination protocols
have been successfully developed for the synthesis of acyclic
diamines,6 cyclic diamines,7 imidazolines,8 imidazolidin-2-
ones,9 indolines,10 pyrrolopyridines,11 pyrrolidines,12 piper-
idines,13 piperidin-2-ones,14 isoxazolidines,15 dihydroisoquino-
lin-1(2H)-ones,16 tetrahydroquinoxalines,17 etc.18 Three-com-
ponent vicinal diamination of alkenes however is a more
powerful method with which to assemble multifunctional
structures from abundant chemical feedstocks, and this
methodology can greatly broaden the availability and utility
of Studer,23 Xu,24 Lin,25 Fu,26 and Morandi.27 In addition,
under oxidative conditions, direct alkylaminative diamination
of alkenes with secondary amines has been developed by Li28
of diamines (Scheme 1a). Muniz et al. have elegantly
̃
developed attractive three-component routes for vicinal
sulfonylaminative diamination of alkenes.19 Subsequently,
Weng,20 Rovis,21 and Michael22 independently reported
interesting approaches to the sulfonylaminative diamination
of alkenes catalyzed by copper, rhodium, or selenophosphor-
amide. As an alternative, the azidative diamination of alkenes is
a good method for the synthesis of useful azidoamines and
such methods have been intelligently exploited by the groups
Received: March 15, 2021
Published: April 1, 2021
https://doi.org/10.1021/acs.orglett.1c00898
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3184−3189
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and Leonori,29 while Zhang30 reported an acetylaminative
diamination of styrenes in the presence of acetonitrile.
Notwithstanding this progress, further development of novel
diamination systems is still necessary.
Information)]. While the Lewis acids that were tested failed
to provide 3a (entry 8),35 the performances of other Brønsted
acids were poorer than that of HPF6 [entry 9 vs entry 5 (details
in the Supporting Information)]. It was also found that the
best yield of 3a was obtained when the reaction was performed
at 70 °C [entries 10 and 11 (details in the Supporting
Information)], and when 1.5 equiv of DEAD was used, a 73%
yield of 3a was obtained (entry 12).
Dialkyl azodicarboxylates are a type of versatile reagent and
are essential building blocks widely used for the synthesis of
complex molecules.31 They have been successfully applied in
the state-of-the-art Mitsunobu reaction and Michael addition
reaction,32 and also as radical acceptors (Scheme 1b). Inspired
by these well-documented three-component vicinal diamina-
tions of alkenes and continuing our ongoing research on the
difunctionalization of alkenes,33 we report here an intermo-
lecular three-component vicinal diamination of vinylarenes
with acetonitrile and dialkyl azodicarboxylates as the nitrogen
sources (Scheme 1c). Dialkyl azodicarboxylates are thought to
be activated by Brønsted acids, and this reaction can
regioselectively produce a range of diversified vicinal diamines
in a one-pot fashion to form two C(sp3)−N bonds.
After the optimal reaction conditions had been determined,
the scope of the reaction was examined (Scheme 2). It was
a
Scheme 2. Substrate Scope of the Diamination Reaction
In our exploration of the intermolecular three-component
vicinal diamination of vinylarenes, we began with the reaction
of styrene and diethyl azodicarboxylate (DEAD) (Table 1).
a
Table 1. Reaction Condition Screening
yield
b
entry
derivation from the standard conditions
(%)
1
2
none
87
57−74
Cu(OAc)2, Cu(acac)2, CuCl2, CuBr, or Cu(OTf)2 was
used in place of Cu(CH3CN)4PF6
3
Fe(OTs)3, Fe(OTf)3, or Fe(OTf)2 was used in place of
Cu(CH3CN)4PF6
57−66
4
5
6
7
8
other tested metals were used in place of Cu(CH3CN)4PF6 51−75
without Cu(CH3CN)4PF6
68
without HPF6
0
0.4 equiv of HPF6 instead of 0.8 equiv
Yb(OTf)3, Zn(OTf)2, Y(OTf)3, Nd(OTf)3, Al(OTf)3, or
Ce(OTf)3 was used in place of HPF6
75
0
9
HBF4, H2SO4, CH3COOH, CF3COOH, HCl, H3PO4, or
HOTf was used in place of HPF6
0−46
a
Reaction conditions: 1 (0.5 mmol), 2a (1 mmol), HPF6 (0.4 mmol),
10
11
12
performed at 50 °C
performed at 80 °C
1.5 equiv of DEAD instead of 2 equiv
70
47
73
and Cu(CH3CN)4PF6 (2 mol %) in CH3CN (2 mL) at 70 °C for 24
h under a nitrogen atmosphere. Isolated yield. 30% thermal ellipsoids
b
c
are shown. 4-Vinylphenyl acetate (1l) was used as the substrate. 1o
(3 mmol), 2a (6 mmol), HPF6 (2.4 mmol), and Cu(CH3CN)4PF6 (2
mol %) in CH3CN (12 mL) at 70 °C for 24 h. Isolated yield.
a
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), HPF6 (0.4
mmol), and Cu(CH3CN)4PF6 (2 mol %) in CH3CN (2 mL) at 70 °C
for 24 h under a nitrogen atmosphere. Isolated yield.
b
d
Diisopropyl azodicarboxylate (2 equiv) was used instead of DEAD.
e
f
Butyronitrile was used as the solvent. Isobutyronitrile was used as
g
the solvent. Benzonitrile was used as the solvent.
The optimal conditions were identified as the reaction taking
place in acetonitrile at 70 °C for 24 h in the presence of a
transition metal salt, Cu(CH3CN)4PF6, and a Brønsted acid,
HPF6 (entry 1).34 Copper salts such as Cu(OAc)2, Cu(acac)2,
CuCl2, CuBr, and Cu(OTf)2 failed to improve the efficiency of
this reaction, but other metals such as Fe, Pd, and Ni provided
similar positive results [entries 2−4, respectively (details in the
Supporting Information)]. When the reaction was carried with
no metal salt, a yield as high as 68% was obtained (entry 5),
but no trace of the desired product (3a) was observed in the
absence of HPF6 (entry 6), a result suggesting that the
Brønsted acid plays a significant role in the reaction.
Decreasing the amount of the Brønsted acid resulted in a
decreased yield of 3a, but increasing the load of HPF6 failed to
improve the yield [entry 7 (details in the Supporting
found that the positions of substituents on the phenyl ring
have little effect on the reaction and the target products can in
all cases be obtained in moderate to high yields. Substrates
with an electron-donating group or an electron-withdrawing
group at the para position of the benzene ring afforded the
corresponding products (3a−3k) in moderate to good yields.
However, when 1l was used as the substrate, the acetyl group
was simultaneously removed under the acidic conditions and
the reaction afforded product 3l with a free phenolic hydroxyl
group. Compounds with a substituent at the meta or ortho
position of the benzene ring produced the corresponding
products (3m−3p) in good to high yields. Styrenes containing
disubstituted aryl groups produced the corresponding products
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(3q−3w), albeit with somewhat lower yields, and 2-vinyl-
naphthalene delivered desired product 3x in 58% yield.
Diamination product 3y can be smoothly produced from
substrate 1y, which is a derivative of estrone, but when
diisopropyl azodicarboxylate was used instead of DEAD, an
only 40% yield of desired product 3z was formed. The reaction
can be performed with butyronitrile, isobutyronitrile, or
benzonitrile as the solvent, affording the corresponding
products (3aa−3ac) in good yields. A 1,2-disubstituted
styrene, β-methyl styrene, smoothly underwent the reaction,
affording the corresponding product (3ad) in moderate yield,
but α,β-dimethyl styrene, 1-methoxy-4-vinyl-benzene, and N-
methyl-4-vinylbenzamide failed to deliver the corresponding
products. When performed on a scale of up to 5 mmol, the
reaction afforded an excellent yield. The structure of product
3a was confirmed by X-ray crystallography.
calculations were performed in an effort to understand the
reaction mechanism at an atomic level. Protonation of DEAD
by H3O+ was initially obtained with no barrier and an
exergonicity of 7.9 kcal/mol, because the reaction took place
with an aqueous HPF6 reagent. Next, we calculated the
reaction pathway starting from the protonated DEAD
(HDEAD) as shown in Figure 1. Similar to the protonation
To explore the practicality of the reaction in organic
synthesis, transformations of the diamination products were
conducted (Scheme 3). The diamination product (3a) can
Scheme 3. Synthetic Application of the Diamination
Products
Figure 1. Gibbs free energy profile of the reaction pathway from
HDEAD. Relative enthalpies are also listed in parentheses. Relative
free energies and enthalpies are given in kilocalories per mole. All of
the optimized structures are calculated at the B3LYP-D3/Def2-
TZVP/(SMD)//B3LYP-D3/Def2-SVP level of theory.
of DEAD, the reaction of the electrophilic HDEAD with the
ethenyl moiety of styrene also shows no barrier (see the
Supporting Information for more details). Interestingly, a six-
membered ring intermediate corresponding to the diazene-
carboxyl group of HDEAD with the ethenyl group of styrene
(int1) was afforded rather than a benzylic carbocation. The
Ritter reaction then proceeded from int1. Transition state TS1
was found with a barrier of 19.8 kcal/mol corresponding to the
nucleophilic attack of acetonitrile, which delivered an ender-
gonic int2. Subsequently, TS2 formed by the addition of water
was found to be the rate-determining step with a barrier of 22.6
kcal/mol. It is noteworthy that TS2 is a concerted transition
state corresponding to the addition of hydroxyl onto the
carbon atom with the transfer of a proton to the nitrogen atom
of acetonitrile; the proton transfer is assisted by the carboxylate
group of HDEAD. According to our previous study, we cannot
exclude the two-water-assisted model for this step.33c The
copper salt might promote the Ritter reaction and assume
other roles, which remain unknown.30
react with methyl 2-bromoacetate to deliver compound 4,
whose N−N bond can be broken under Cs2CO3/CH3CN
conditions to produce the carbamate (5).36 When subjected to
basic conditions with KOH and MeOH, the diamination
product (3a) can be successfully converted into a phenyl-
substituted imidazolidin-2-one (6) in 65% yield,37 and the
diamination product (3o) can be smoothly cyclized under
Ullmann conditions to give a substituted 1,2,3,4-tetrahydro-
cinnoline (7).38 The structures of compounds 6 and 7 have
been confirmed by X-ray crystallography.
In this reaction, we hypothesized that, under strong
Brønsted acid conditions, DEAD is protonated by HPF6 and
affords a positively charged intermediate (Scheme 4). This
electrophilic intermediate then reacts with styrene to afford a
benzylic carbocation, and the diamination product is formed
through a Ritter reaction.39 Density functional theory (DFT)
In conclusion, we have developed a regioselective inter-
molecular, three-component vicinal diamination of styrenes
under acidic conditions. Commercially available azodicarbox-
ylates serve as a nitrogen source, and acetonitrile not only was
used as the solvent but also was engaged in the subsequent
Ritter reaction to produce the vicinal amines in moderate to
excellent yields. This reaction features good substrate scope
and functional group tolerance. Synthetic applications of this
direct vicinal diamination products and theoretical studies have
been conducted.
Scheme 4. Proposed Mechanism
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Notes
ASSOCIATED CONTENT
* Supporting Information
■
sı
The authors declare no competing financial interest.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00898.
ACKNOWLEDGMENTS
■
Supported by the NSFC (Grants 21871258, 21922112, and
22001251), the Haixi Institute of CAS (Grant CXZX-2017-
P01), the Scientific Research Foundation of Fujian Normal
University in China, and Innovative Research Teams Program
II of Fujian Normal University in China (IRTL1703).
Reaction optimization, experimental procedures, full
analysis data for new compounds, and copies of NMR
spectra (PDF)
Accession Codes
CCDC 2014478, 2032215, and 2032245 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
DEDICATION
In memory of Professor Kilian Mun
■
̃
iz.
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AUTHOR INFORMATION
Corresponding Author
■
Hongli Bao − Key Laboratory of Coal to Ethylene Glycol and
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Fujian Institute of Research on the Structure of Matter,
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China
Mong-Feng Chiou − Key Laboratory of Coal to Ethylene
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350002, P. R. China; orcid.org/0000-0001-7074-9285
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Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou, Fujian 350002, P. R.
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