Metal-Free Geminal Difunctionalization of Diazocarbonyl Compounds: A One-Pot Multicomponent Strategy for the Construction of α,β-Diamino Carbonyl Derivatives

Article abstract of DOI:10.1002/chem.201800555

An unprecedented three-component domino oxidative coupling of diazocompounds for the efficient synthesis of α-azido-β-amino esters with non-activated dimethylamino compounds and simple TMSN₃ was achieved. The main features of this method include metal-free catalysis, satisfactory functional group tolerance, general applicability in complex molecule architectures, and excellent diastereoselectivity in the presence of chiral auxiliaries. In addition, several related control experiments have been conducted to investigate the reaction mechanism.

Full text of DOI:10.1002/chem.201800555

A Journal of
Accepted Article
Title: Metal-Free Geminal Difunctionalization of Diazocarbonyl
Compounds: A One-Pot Multicomponent Strategy for the
Construction of α,β-Diamino Carbonyl Derivatives
Authors: Dan Zhu, Yuan Yao, Rong Zhao, Yang Liu, and Lei Shi
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To be cited as: Chem. Eur. J. 10.1002/chem.201800555
Link to VoR: http://dx.doi.org/10.1002/chem.201800555
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Metal-Free Geminal Difunctionalization of Diazocarbonyl
Compounds: A One-Pot Multicomponent Strategy for the
Construction of ,-Diamino Carbonyl Derivatives
Dan Zhu, Yuan Yao, Rong Zhao, Yang Liu, and Lei Shi*
Abstract: An unprecedented three-component domino oxidative
coupling of diazocompounds for the efficient synthesis of α-azido-β-
amino esters with non-activated dimethylamino compounds and
simple TMSN3 was achieved. The highlighted features of this method
are in terms of metal-free catalysis, satisfactory functional group
tolerance, general applicability in complex molecule architectures,
and excellent diastereoselectivity in the presence of chiral auxiliaries.
Besides, several related control experiments have been conducted
reasonably to investigate the reaction mechanism.
α,β-Diamino acid derivatives as important functional moieties are
present in a number of biologically relevant molecules and natural
products (Figure 1), which have been widely applied in the field of
medicinal chemistry. In addition, they can also be used as highly
privileged synthetic building blocks in the bioactive and stability
modifications of polypeptides.[1] Due to the considerable interest
to the scientific community, dozens of methods have been
developed for the synthesis of α,β-diamino carbonyl derivatives
(Scheme S-1 in the supporting information).[2]
Diazo groups and azido groups have been used extensively
as versatile synthetic intermediates and critical synthons[3] in the
synthesis of diverse nitrogen-rich natural products, and have also
been successfully employed as the excellent reporters to the rapid
incorporation of nitrogenous groups in chemical biology.[4] In
contrast to azido groups, diazo groups, which are smaller than
analogous azido groups, are found in many natural products
(Figure S-1 in the supporting information)[5] and display a broader
range of reactivity and selectivity.[6]
In recent years, much attention has been paid to
diazocompounds bearing electron-withdrawing substituents such
as α-diazocarbonyl compounds due to their greater stabilities as
compared to the alkyl diazo compounds. Through the thermal or
photochemical cleavage of the carbon-nitrogen bond releasing
thermodynamically stable dinitrogen as a leaving group, α-
diazocarbonyl compounds generate carbenes carrying a carbonyl
Figure 1. Selected natural products containing an α,β-diamino acid moiety.
substituent which is highly reactive, and in case of transition
metal-carbenes also highly chemo-, regio-, and stereoselective.
Their versatility in chemical transformations[6c] (Scheme S-2 in the
supporting information) including cycloadditions, insertion
reactions, ylide formations, and the Wolff rearrangements, makes
them important reagents and precursors for organic synthesis. On
the other hand, α-diazocarbonyl compounds are also served as
the significant radical acceptors, and can be trapped by the in situ
generated radical toward crucial chemical bond formation.[7]
Among various strategies for the reported diazo-based
transformations, the introduction of dual functionality to the α-
diazo carbonyl compounds in a geminal fashion has received
increasing attention due to the simultaneous formation of two
geminal chemical bonds.[6]
[*] D. Zhu, Dr. Y. Yao, R. Zhao, Dr. Y. Liu, Prof. Dr. L. Shi
MIIT Key Laboratory of Critical Materials Technology for New
Energy Conversion and Storage, School of Chemistry and
Chemical Engineering, Harbin Institute of Technology, Harbin
150001 (China)
However, despite enormous progress in this field, the
geminal difunctionalization of α-diazo carbonyl compounds
through a multicomponent process, especially when done in a
stereocontrolled manner, still remains less explored and
challenging. In this regard, an array of transition-metal-catalyzed
multicomponent reactions of diazo carbonyl compounds have
been investigated extensively since the pioneering work of Hu and
Gong, by virtue of electrophilic trapping of a wide variety of active
oxonium ylides, ammonium ylides or zwitterionic intermediates.[8]
In 2015, Liu and Tan reported an enantioselective
E-mail: lshi@hit.edu.cn
Homepage: http://homepage.hit.edu.cn/shilei
D. Zhu, R. Zhao, Prof. Dr. L. Shi
Shenzhen Graduate School, Harbin Intitute of Technology, Shenzhen
518055 (China)
Prof. Dr. L. Shi
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071 (China)
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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Table 1. Optimization of the reaction conditions.a
multicomponent reaction of diazooxindoles, nitrosoarenes, and
nitroalkenes using a newly developed bis(thiourea) hydrogen-
bond catalyst.[9] Recently, Wan successfully developed a Co-
catalyzed three-component tandem reaction of α-diazo esters
with styrenes and tertiary amines using tert-butyl hydroperoxide
(TBHP) as the only oxidant, which involved the oxidative multi-
component coupling between cobalt-based carbene radicals and
α-amino alkyl radicals to yield β-ester-γ-amino ketones.[10] Shortly
thereafter, Li, Tu and Jiang jointly demonstrated two domino
oxidative three-component couplings of α-diazo ketones in
moderate to good yields to construct functionalized α-oxy-β-
amino ketones and α,β-diamino ketones.[11] Meanwhile, Szabó
disclosed two examples of rhodium-catalyzed three-component
coupling sequences of α-diazo ketones to access a broad range
of gem-oxyfluoride or gem-oxytrifluoride products.[12] More
recently, Zhou invented silver-catalyzed three-component
Entry
Oxidant (equiv)
Solvent
Yieldb (%)
1
2
PIDA (2.0)
PIFA (2.0)
DCM
DCM
Trace
None
7
3
BI-OH (2.0)
BI-OH (2.0)
BI-OH (2.0)
BI-OH (2.0)
BI-OH (1.2)
BI-OH (1.2)
BI-OH (1.2)
BI-OH (1.2)
DCM
4
MeCN
THF
42
5
Trace
None
72
reaction
of
diazoketones,
anilines
and
N-
6
Toluene
MeCN
MeCN
MeCN
MeCN
fluorobenzenesulfonimide (NFSI), providing an interesting gem-
aminofluorination approach in moderate to good yields.[13]
7
Herein,
we
report
metal-free
oxidative
geminal
8
64c
carboazidation of α-diazo carbonyl compounds with readily
accessible tertiary amines and commercially available TMSN3 to
afford the valuable α,β-diamino acids derivatives with high
structural diversity and complexity. The versatile, operationally
simple and highly efficient one-pot three-component approach for
the synthesis of α-azido-β-amino carbonyl derivatives results in
the concomitant construction of C–C and C–N bonds, providing
carboazidation products in moderate to excellent yields. In
contrast to traditional approaches towards α,β-diamino acids, the
attractive feature of this method is that the construction of the
carbon skeleton and the introduction of nitrogen atoms take place
in one-pot multicomponent procedure, thus providing an easy
access for highly efficient construction of α-azido-β-amino
carbonyl derivatives from simple substrates under mild reaction
conditions. To the best of our knowledge, this represents the first
example of an effective multicomponent sequence that rapidly
affords α-azido-β-amino carbonyl derivatives.
We initiated our studies by investigating the three-component
reaction between N,N-dimethylaniline (2a), ethyl diazoacetate
(1a) and TMSN3 under a nitrogen atmosphere using kinds of
hypervalent iodine reagents as the only oxidant in DCM at room
temperature. The experiment results show that when use the BI-
OH as the oxidant, the reaction can give the desired product in a
7% isolated yield (Table 1, entry 3). Encouraged by this result,
various solvents have been screened immediately to optimize the
reaction conditions. In stark contrast to toluene, DCM, and THF,
using acetonitrile as the solvent can significantly increase the
yield of the reaction to 42% (Table 1, entry 4). Further
improvement in the yield was achieved carefully by decreasing
the stoichiometric ratio of the oxidant to 1.2 (Table 1, entry 7).
However, replacing the TMSN3 to NaN3 is proved to be useless in
the transformation (Table 1, entry 10). Consequently, the reaction
condition described in entry 7 was selected as the standard
condition. It is worth noting that the corresponding α-azido-β-
amino carbonyl derivatives as simple but polyfunctional
molecules represent a significant synthetic challenge owing to the
presence of contiguous stereocenters in a flexible acyclic
molecule. The ester and the azido group can serve as versatile
handles for further transformations. Interestingly, before our
investigation, the same carboazidation product 3aa could be
9
37d
10
Nonee
[a] The reaction condition: N,N-dimethyl aniline (2a, 0.3 mmol), TMSN3 (2.0
equiv, 0.6 mmol), N2CHCO2Et (2.0 equiv, 0.6 mmol), oxidant, solvent (2 mL),
under N2 condition. [b] Isolated yield. [c] N2CHCO2Et (3.0 equiv, 0.9 mmol).
[d] TMSN3 (3.0 equiv, 0.9 mmol). [e] Choose NaN3 as the reaction reagent.
obtained only through three successive reactions in a 38% overall
yield (76% x 68% x 74%).[14]
With the optimized reaction condition in hand (Table 1, entry
7), we then set out to evaluate the substrate scope of this reaction
with respect to the applied tertiary amines. As shown in Scheme
1, various functional groups including halides, methyl, azo, ketone,
aldehyde, and alcohol were well tolerated, furnishing the
corresponding α-azido-β-amino carbonyl compounds without
difficulty. It's worth mentioning that N-methylene of the
tetrahydroisoquinoline (2l) was also well achieved the expectant
result under the standard reaction condition and get the
corresponding product (3al) with a single diastereomer based on
the 1H NMR and 13C NMR analysis. As far as we know,
tetrahydroisoquinolines (0.55 V vs. SCE)[15] have lower oxidation
potentials than similar N,N-dimethylanilines (0.84 V vs. SCE).[16]
Even so, the tetrahydroquinoline moiety is present in various
natural products, and exhibit a broad range of biological activities,
which magnified its value perfectly.[17] Notably, the challenging
late-stage application of complex biologically important
compounds and architectures, such as steroid (3am),
mifepristone (3an) and dihydroartemisinin derivatives (3ao and
3ap) is all right. Moreover, the introduction of the azide group into
such compounds maybe conductive to their drug or biological
activity at some level. Modification of steroidal and sesquiterpene
drugs provides an efficient route for the fine-tuning of their
biological activity. Therefore, our method was applied to the late-
stage carboazidation to afford the desired products in 17-54%
yields. Meanwhile, this transformation highlights the
chemoselectivity of the method in the presence of
carbon−hydrogen bonds, olefins, alkynes, and carbonyls, which
can react with α-diazocarbonyl compounds. The utility of the
transformation is demonstrated in the late-stage site-selective
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functionalization of natural products and pharmaceuticals,
allowing rapid derivatization for investigation of structure−activity
relationships.
Scheme 2. Scope of various diazocompounds.
Scheme 1. Scope of this reaction with respect to the applied tertiary amines. [a]
2a: 30 mmol.
We then turned our attention to examining the applicability of
various diazocompounds. As shown in Scheme 2, the attached
substituent groups on the phenyl ring not only electron-donating
but also electron-withdrawing were compatible, and gave the
expectant products in satisfactory yields (3ba-3ga). Besides the
above-mentioned
diazoesters
and
α-diazo
carbonyls,
Scheme 3. Control experiments and mechanistic studies. [a] Doyle’s work.
diazoamides can also carry out the reaction well (3ha).
Next, we focused on the development of an asymmetric
variant of this unprecedented three-component reaction. As a
large number of chiral auxiliaries can be introduced at the ester
moiety of α-diazo compounds, asymmetric induction of central
chirality during our multicomponent reactions of α-diazocarbonyl
compounds might be also anticipated.[18] Kinds of chiral auxiliary
of α-diazocarbonyl compounds have been detected in our system.
It is desirable that both oxazolidinone (3ka) and camphorsultam
can get the objective product as an essentially single
stereoisomer in 44% and 22% yield respectively. We think the
possible reason for the low yield of the desired products (such as
1k, 1l and 1m) is the existence of the relatively bulky ester.
Gratifyingly, a noteworthy observation is that the absolute and
relative configuration of 3la and 3ma by X-ray single crystal
diffraction analysis was unambiguously confirmed, a further
reminder of the feasibility of the method to generate high
selectivity induced by chiral auxiliaries.[19] The successful
incorporation of the azide group with high selectivity will be
potential and of high value in their bioactivity and other properties.
Compare to the above, using the piperitol and steroid (3ia and
3ja) as the chiral auxiliary can nearly not induce the
Several control experiments (Scheme 3) were conducted to
reveal the reaction mechanism. The radical inhibition experiments
were firstly carried out with the use of diverse radical inhibitors.
Compared to the partial inhibition of 1,4-dinitrobenzene and
BHT(2,6-di-tert-butyl-4-methylphenol), the hydroquinone can
totally inhibit, suggesting a radical pathway largely. Kinetic and
product isotope effects were then calculated to investigate the
process of the C–H cleavage at the α-position to nitrogen. We
found that the obtained KIE and PIE values were closely related
with those for the reaction reported in the Doyle’s work,[20]
suggesting that they could share the reaction mechanism as
shown in Scheme 4. The radical 5 was formed in a general
oxidant way, followed by the SET which is accompanied by a
competing backward SET to generate the critical intermediate
amine radical cation 6. It will clearly reduce the bond dissociation
energy (BDE) and the pKa of α-C–H bond to the nitrogen,[21]
making it certainly practicable in the next deprotonation of the
amine radical cation to form α-aminoalkyl radical 7. In our reaction,
we always find a demethylation phenomenon. We speculated that
it was maybe derived from immonium ion. Then we used the
HCHO to capture the immonium ion to prove the hypothesis
through an isotopic scrambling experiment. The isolated product
lacked any deuterium labeling in methylene group explicitly
1
stereoselectivity with a diasteromeric ratio of 1:1 base on the H
NMR and 13C NMR analysis.
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radical or ionic mechanism. Further investigations will continue to
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Scheme 4. Proposed reaction mechanism.
In conclusion, we have described an unprecedented three-
component domino oxidative coupling of dimethylamino
compounds with diazocompounds and simple TMSN3 for the
synthesis of α-azido-β-amino esters under a mild and efficient
condition. This novel method realized the direct α-C(sp3)–H
azidation of tertiary amines without any metal catalysis and offers
a facile and flexible access to privileged amino acid precursors.
The mild reaction conditions, cheap reaction reagents, excellent
functional group compatibility, and high levels of substrate-
directed diastereocontrol provide an opportunity for late-stage
azidation of complex molecules. More importantly, the
introduction of the oxazolidinone and camphorsultam as the
auxiliary attached to the diazocarbonyl compounds can
successfully impart its chirality, leading the corresponding
products with an essentially single stereoisomer. Further
investigations on related reactions to expand the utility of the
hypervalent iodine reagents, and catalytic enantioselective
version of the transformation are currently underway in our
laboratory.
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Acknowledgements
The work was financially supported by the “Hundred Talents
Program” of Harbin Institute of Technology (HIT), the
“Fundamental Research Funds for the Central University”
(HIT.BRETIV.201502), the NSFC (21202027), the NCET (NCET-
12-0145), the Open Project Program of Hubei Key Laboratory of
Drug Synthesis and Optimization, Jingchu University of
Technology (no. opp2015ZD01), and the “Technology Foundation
for Selected Overseas Chinese Scholar” of Ministry of Human
Resources and Social Security of China (MOHRSS). The authors
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Keywords: metal-free • C‒H functionalization • geminal
carboazidation • three-component coupling • hypervalent iodine
reagents
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Dan Zhu, Yuan Yao, Rong Zhao, Yang
Liu, and Lei Shi*
Page No. – Page No.
Metal-Free Geminal
difunctionalization of Diazocarbonyl
Compounds: A One-Pot
Multicomponent Strategy for the
Construction of ,-Diamino Carbonyl
Derivatives
An unprecedented three-component domino oxidative coupling of diazocompounds
for the efficient synthesis of α-azido-β-amino esters with non-activated
dimethylamino compounds and simple TMSN3 was achieved. Meanwhile, this
reaction offers a straightforward approach for the asymmetric synthesis of α-azido-
β-amino esters in the presence of chiral auxiliaries.
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