Iridium catalyzed acceptor/acceptor carbene insertion into N-H bonds in water

Article abstract of DOI:10.1039/c7ob00177k

The chemistry of A and D/A carbenes (D and A are donor and acceptor groups, respectively) is known to a great extent in the literature. Nevertheless the chemistry of the A/A class of carbenes is less explored, although the A/A class of carbenes is more im

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Iridium Catalyzed Acceptor/Acceptor Carbene Insertion into the N−H Bond
in Water Medium
Kankanala Ramakrishna and Chinnappan Sivasankar*
Catalysis and Energy Laboratory, Department of Chemistry
Pondicherry University (A Central University), Puducherry 605014, India
Email: siva.che@pondiuni.edu.in
ABSTRACT:
The chemistry of A and D/A carbenes ( D and A are donor and acceptor groups respectively) are
known to the great extent in the literature, nevertheless the chemistry of A/A class of carbenes
are less explored although A/A class of carbenes are more important in the natural product
synthesis. Known catalysts for A/A carbene chemistry is also less in number and found to be
efficient only in typical organic solvents. These limitations prompted us to search for new
catalysts and environmentally benign reaction conditions for A/A class of carbenes. The present
study revealed that the [(COD)IrCl]2 is found to be an efficient catalyst for A/A and Pd2(dba)3
for D/A class of carbenes for insertion into N−H bond in water medium under mild reaction
conditions. Reactivity comparison study with different class of carbenes revealed that the silver
based catalysts can be the right choice for D/D class of carbenes insertion into N−H bond in
water medium. A large number of αꢀamino malonates and amino esters which are important for
the synthesis of heterocycles and several natural products have been synthesized by following
current methodology and characterized using standard analytical and spectroscopic techniques.
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Introduction:
Metal complexes mediated carbene reactions have been an important tool in the synthetic
organic chemistry owing to their potential applications.1,2 In general different carbenes are
generated from their corresponding diazo compounds mediated by transition metal complexes as
catalysts (nevertheless majority of NHC class of carbenes are synthesized by other methods).3
Typical carbene related reactions are carbene insertion into X−H (X= NR, O, S, CR3, SiR3 or
BR2) bond and cyclization etc.4,5 These typical carbene reactions provide practically viable route
for the construction of new C−C and C−X (X=hetero atom) bonds under mild reaction
conditions.6 Carbene reaction with olefin provides an easy way to the construction of strained
three membered rings (carbene cyclization with olefin), which are serving as key intermediates
for synthesis of drug molecules and natural products in pharmaceuticals.7–9
Based on the nature of αꢀsubstituents (donor (D), acceptor (A)), the carbene precursors namely
diazo compounds can be classified as donor/donor (D/D), donor/acceptor (D/A), and
acceptor/acceptor (A/A) (Scheme 1) as they display different reactivity pattern.10,11 Among these
three class of diazo compounds, so far only D/A diazo compounds have been intensely studied
owing to their more reactivity and moderate thermal stability. These diazo compounds (D/A)
react with suitable substrates under mild reaction conditions with excellent chemoselectivity12–15
and enantioselectivity.16–20 However carbenes having A/A substituents are very important owing
to their immense applications in the total synthesis including heterocycles.21–24 Nevertheless the
chemistry of carbenes having A/A and D/D substituents has not been explored owing to their
high thermal stability and low reactivity of A/A carbene source and low thermal stability and
high reactivity of D/D carbene source (Scheme 1).10 Among these A/A and D/D carbenes
sources, the A/A carbene sources display interesting reactivity patterns owing to their good
2

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thermal stability and scope for wide functional groups. Owing to the high thermal stability of
A/A carbene source, one has to use catalysts such as Rh, Ir, Co or Ru under harsh reaction
conditions especially for CꢀH activation and heterocycles construction.25–29
Scheme 1. Overview of classification of different diazo compounds
The A/A carbenes have also been used for cyclization of alkenes and alkynes,30–35 and carbene
insertion into N−H and O−H bonds of amides and acids respectively are known only in organic
solvents.12,36–38 So far only Rh based catalysts and harsh reaction conditions have been used for
A/A carbenes insertion into N−H bond and produced poor to moderate yields,36–39 these harsh
reaction conditions resulted in low selectivity and produced several unwanted side products.10 In
this line, so far no reports are available in the literature for the utilization of A/A carbenes
insertion in an environmentally benign reaction conditions.
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Scheme 2. Known carbene insertion into N−H bond in aqueous medium
Francis et al. successfully utilized Rh catalyzed D/A carbene insertion into N−H bond as a tool
to modify the protein,40 and this strategy has become one of the important methodologies for
protein modification and labelling.41–43 Thereafter significant advancements have been made
with respect to finding new catalysts for the reaction of D/A carbenes insertion into N−H bond in
aqueous medium especially for protein modification (Scheme 2).44–47 In this line, recently our
group also reported an efficient method for synthesis of amino phosphonates in aqueous medium
from diazo phosphonates and anilines catalyzed by Cu(I) catalyst.48 Although the D/A carbenes
used in the protein chemistry, A/A carbenes have not been used therefore in order to extend the
scope of A/A carbene reactions for protein labeling, protein modification and in total synthesis,
some effective catalysts which works under mild reaction conditions with high selectivity in
aqueous medium are to be discovered. By considering the importance of A/A carbene insertion
reactions and continuation of our research on carbene related reactions13,15,48,49 herein we report a
feasible method for A/A carbene insertion into N−H bond in water medium under mild reaction
conditions using Ir(I) complex as a catalyst. The already known Ir complexes are capable of
inserting only D/A class of carbenes into N−H bond in organic solvents therefore our
methodology would be more useful in the synthetic organic chemistry.50,51
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Results and discussion:
We have chosen diethyl 2ꢀdiazomalonate (1a) as a A/A carbene source, which is highly stable
among all commonly used carbene sources and relatively less explored.11 For the sake of
reactivity comparison, methyl 2ꢀdiazoꢀ2ꢀ(4ꢀmethoxyphenyl)acetate (2) and 4,4'ꢀ
(diazomethylene)bis(methoxybenzene) (3) precursors have also been used in the present study as
the representative examples for D/A and D/D carbene sources respectively (Table 1). We have
also chosen different transition metal complexes and salts as catalysts for carbene insertion
reaction in water medium.
Table 1. Screening of the various catalysts for carbene insertion into N−H bond in water medium
entrya
catalyst
catalyst load
A/A
D/A
D/D
(mol %)
time yield(%) time yield(%) time yield(%)
1
2
3
4
5
6
7
8
9
[(CH3CN)4Cu]ClO4
Cu(OTf)2
2
2
1
1
1
1
2
2
1
2
12 h
12 h
24 h
24 h
12 h
24 h
24 h
24 h
24 h
24 h
51
47
ND
trace
81
trace
trace
ND
ND
ND
1 min
1 min
1 min
4 h
37
28
34
83
87
61
54
trace
90
89
1 min
1 min
24 h
24 h
24 h
24 H
5 min
1 h
<10
<10
<10
trace
<10
<10
56
37
17
26
Rh2(OAc)4
[(COD)RhCl]2
[(COD)IrCl]2
[(pꢀcymene)RuCl2]2
AgOTf
6 h
24 h
24 h
24 h
30 min
6 h
AuCl
Pd2(dba)3
PdCl2
24 h
8 h
10
aAll the reactions are carried out with 1 mmol of aniline and 1.1 mmol of diazo compound. Yield: Pure compound
after column chromatography.
In case of A/A diazo compounds, the [(COD)IrCl]2 produced 81% (Table 1, entry 5) of expected
N−H inserted product over 12h while other catalysts produced less yields and taken more time
(Table 1). In case of D/A diazo compounds, the reaction was completed over 30 min and offered
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90% of N−H inserted product while Pd2(dba)3 was used as a catalyst (Table 1, entry 9) whereas
other catalysts produced either comparable amount of yields or lesser than the yield observed for
Pd2(dba)3. In case of D/D diazo compounds, the AgOTf offered 56% of N−H inserted product
(Table 1, entry 7) while other catalysts produced relatively less yields.
Scheme 3. Reaction of A/A diazo compound in water catalyzed by [(COD)IrCl]2 (O−H
insertion)
When we conducted the reaction using [(COD)IrCl]2 as a catalyst in the absence of amine
source, the A/A diazo compounds offered exclusively 77% of water O−H inserted product (8)
over 6 h (Scheme 3). However when we conducted the reaction in the presence of aniline, we
have not observed any water O−H inserted product. From the above study it can be noted that the
carbene insertion into N−H bond seems to be faster than the carbene insertion into O−H bond of
water.
Subsequently we attempted to explore the scope of anilines for A/A diazo compounds in water
medium. In order to demonstrate the substrate scope for different anilines, we screened a large
number of anilines with electron donating and electron withdrawing groups (Scheme 4). All the
anilines (5b−5f) having electron donating groups offered N−H inserted products in excellent
yields. We observed highest yield (98%) in case of 2,4,6ꢀtrimethyl aniline (5e) and lowest yield
(88%) with para toluidine (5b). To our surprise, steric factor does not affect the product yields,
for an example 2,6ꢀdiisopropyl aniline (5d) offered excellent yield (96%).
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Scheme 4. Scope of anilines for A/A carbene insertion into N−H bond in water medium
catalyzed by [(COD)IrCl]2
In case of electron withdrawing groups (5g−5s), among all the screened anilines having electron
withdrawing groups, 2ꢀnitro and 4ꢀiodo aniline offered 96% yield (5i and 5o). All the halogen
substituted anilines offered good yields (5g−5i and 5o−5r). Other functional groups such as nitro
and acetyl does drastically affect the yields (5j−5n). Among all the nitro anilines, 2ꢀnitro aniline
offered excellent yield (96%). In case of amino benzo nitrile, we observed 90% yield, similarly
trifluromethyl aniline offered very good yield 95% (5k). Although aniline derivatives offered
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good to excellent yields, aliphatic amines such as benzyl amine and hetero aromatic amines (2ꢀ
aminopyridine) offered trace amount of N−H inserted product.
After screening different anilines, we focused our studies on the scope of different A/A diazo
compounds. We have chosen 4ꢀnitro aniline to react with various A/A diazo compounds
(Scheme 5) owing to the compatibility in handling. When we used dimethyl 2ꢀdiazomalonate,
the reaction offered N−H inserted product in 71% yield over 12 h (9b) (Figure S1). Whereas
ethyl 2ꢀdiazoꢀ3ꢀoxobutanoate offered good yield (79%) over 12 h (9c), 3ꢀdiazopentaneꢀ2,4ꢀdione
diazo offered N−H inserted product in 77% yield over 12 h (9d) and ethyl 2ꢀdiazoꢀ3ꢀoxoꢀ3ꢀ
phenylpropanoate offered 87% yield over 18 h (9e). We have also used other diazo compounds
such as ethyl 2ꢀdiazoꢀ2ꢀ(4ꢀnitrophenyl)acetate and the reaction proceeded slowly to offered 74%
yield over 24 h (9f).
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Scheme 5. Scope of anilines for A/A carbene insertion into N−H bond in water medium
catalyzed by [(COD)IrCl]2
Scheme 6. Derivatization of amino benzoic acids using A/A carbene insertion into N−H bond in
water medium catalyzed by [(COD)IrCl]2
After examining the substrate scope for Ir(I) catalyzed A/A carbene insertion into N−H bond in
water medium, our interest turned towards derivatization of some biologically important
molecules. In this line as representative substrates, we have chosen 4ꢀaminobenzoic acid and 4ꢀ
aminoꢀ2ꢀhydroxybenzoic acids (anti tuberculosis agent), which are biologically and synthetically
important molecules52,53 and produced expected N−H inserted product (78% (12) and 71% (13)
respectively) with A/A type carbenes over the period of 12 h (Scheme 6). Apart from these
molecules, we have also attempted to derivatize some aliphatic amino acids, nevertheless owing
to the limitation of this method on aliphatic amines we ended up with water inserted product (8).
In conclusion, we have developed an efficient green method for A/A type carbene insertion into
N−H bond of various anilines in water medium. In order to achieve this, we screened many
catalysts for A/A, D/A and D/D carbene insertion into N−H bond of aniline in water medium and
we found that [(COD)IrCl]2, Pd2dba3 and AgOTf are efficient catalysts for A/A, D/A and D/D
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carbenes respectively. Using our developed methodology, we have synthesized a large number of
αꢀamino diesters and fully characterized. On the way to extend the scope of present
methodology, we screened variety of A/A diazo compounds and characterized the corresponding
products using standard analytical and spectroscopic techniques. In the near future, this novel
methodology may provide some useful applications for the synthesis of heterocycles and protein
labelling, and modification in water medium.
ACKNOWLEDGMENT
C. S gratefully acknowledges the University Grants Commission, New Delhi, India for the
financial support (MRPꢀMAJORꢀCHEMꢀ2013ꢀ1179). K.R. gratefully acknowledges the UGC
for a Senior Research Fellowship. We thank the Central Instrumentation Facility, Pondicherry
University, for NMR spectra and DSTꢀFIST for the ESIꢀMS and singleꢀcrystal Xꢀray diffraction
facility.
Electronic supplementary information (ESI) available
Analytical data, 1H, 13C NMR Spectra and Xꢀray crystallographic data.
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TOC
Highly stable acceptor/acceptor type of carbenes can be inserted into N−H bond of aromatic
amines using Ir(I) catalyst in water medium.
15