Chemoselective Carbene insertion into the N-H Bond over O-H Bond Using a Well-Defined Single Site (P-P)Cu(I) Catalyst

Article abstract of DOI:10.1021/acs.orglett.5b01776

Phosphine-coordinated air-stable Cu(I) catalyst (1) has been synthesized and characterized. Catalyst 1 is found to be active toward highly chemoselective carbene insertion into the N-H bond over the O-H bond and also over the formation of olefins when num

Full text of DOI:10.1021/acs.orglett.5b01776

Letter
pubs.acs.org/OrgLett
Chemoselective Carbene insertion into the N−H Bond over O−H
Bond Using a Well-Defined Single Site (P−P)Cu(I) Catalyst
Kankanala Ramakrishna, Mani Murali, and Chinnappan Sivasankar*
Catalysis and Energy Laboratory, Department of Chemistry, Pondicherry University, Pondicherry 605014, India
*
S Supporting Information
ABSTRACT: Phosphine-coordinated air-stable Cu(I) catalyst
1) has been synthesized and characterized. Catalyst 1 is found
(
to be active toward highly chemoselective carbene insertion into
the N−H bond over the O−H bond and also over the formation
of olefins when numerous aminophenols were treated with a
variety of α-aryl diazoesters under normal experimental
conditions.
he transition-metal-mediated carbene insertion into the
Nevertheless, these systems have suffered either by low yield or
low selectivity.
T
heteroatom−H bond has received significant interest in the
1
synthetic community because it leads to the formation of
In this regard, we herein report highly chemoselective carbene
insertion into the N−H bond over the O−H bond and also over
the formation of olefins from carbene dimerization using a well-
defined novel (P−P)Cu(I) ((P−P = 2,8-dibromo-4,6-bis-
2
ubiquitous C−X (X = C, N, O, S, B, and Si) bonds. In particular,
carbene insertion into the N−H bond caters the α-amino acid
3
derivatives and versatile building blocks. Although the first
4
(
diphenylphosphanyl)-5-methyl-10,11-dihydro-5H-dibenzo-
catalytic N−H insertion was reported by Yates using copper
5
[b,f ]azepine (L1)) catalyst.
bronze as a catalyst and followed by Saegusa et al. and Nicoud et
6
The copper(I) catalyst was prepared from an equimolar
al. using CuCN as a catalyst, it has been neglected owing to the
21
22
mixture of ligand(L1) and [Cu(CH CN) ]ClO in acetoni-
emergence of Rh as a powerful catalyst for carbene insertion into
3
4
4
7
trile (Scheme 1). This novel complex was characterized and
the N−H bond. Cu received attention after Per
́
ez et al.’s repor8t
on the Cu(I)−homoscorpionate system for N−H insertion.
9
Scheme 1. Preparation of Copper(I) Complex (Catalyst 1)
Later, researchers developed new Cu(I)-based homogeneous,
1
0
11
heterogeneous, biphasic, and asymmetric versions of
1
2
catalysts. In recent years, chemists have started working with
larger and structurally more complex molecules than ever before.
To deal with the structurally complex molecules, chemoselective
catalytic systems have to be developed that are able to catalyze
selective carbene insertion into X−H bonds even in the presence
of other functional groups without protection and deportation
strategies. In this direction, few catalysts have been developed for
selective X−H insertion in the presence of other functional
13
groups like alkene and alkyne. Apart from Rh and Cu catalysts,
researchers have used Ru, Fe, Pd, Ir, Au, and Ag
14
15
16
17
18
3
conformed using various standard spectroscopic techniques. A
single peak was observed at 14.2 ppm in 31P NMR for the
coordinated phosphorus of ligand L1 in complex 1, whereas a
peak at 18.3 ppm was observed for the free ligand L1.
The single-crystal X-ray studies of complex 1 revealed that
the geometry around the copper(I) ion is slightly deviated from
tetrahedral environment (Figure 1), which is commonly
observed for copper(I) complexes. More interestingly, the
complex 1 is air stable unlike most of the Cu(I) complexes.
supported with N, O, and NHC based ligands. When we look at
this chemistry microscopically, we see that chemists have
neglected the phosphorus-based ligands in this area of research,
though phosphorus ligands have shown excellent applications in
23
1
9
C−H activation and many other significant organic reactions.
In practice, the phosphorus ligands are not useful for carbene
9
a,16a,
insertion reactions.
To the best of our knowledge,
Jørgensen and co-workers have used an in situ generated3
phosphorus-based Cu(I) complex for N−H insertion reactions.
Recently, Per
́
ez and co-workers have used tris(phosphino)borate
Received: June 20, 2015
20
ligand based Cu(I) complex for N−H insertion reactions.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Various Catalysts for Chemoselective
N−H Insertion
time
(h)
yield (%) (N−
a
entry
catalyst
H/OH)
dimer
b
1
(CH CN) CuClO
4
5
8
4
56/8
36
52
25
3
4
2
b,c
(CH CN) CuClO + 2PPh
3
18/−
48/11
3
4
4
3
(CH CN) CuClO + 1,10-
3 4 4
phenanthroline
Figure 1. Molecular structure of copper(I) complex; thermal ellipsoids
are set at 50% probability. Perchlorate anion and hydrogen atoms are
omitted for clarity. Important bond lengths (Å) and bond angles (deg):
Cu1−P1 2.247(3), Cu1−P2 2.249(2), Cu1−N2 2.059(8), Cu1−N3
4
5
(CH CN) CuClO + dppe
12
6
53/6
27
13
3
4
4
catalyst 1
83/−
a
2
.022(9), P1−Cu1−P2 115.90(10), P1−Cu1−N2 111.0(2), P1−Cu1−
All the reactions are carried out with 0.5 mmol (with respect to 2-
aminophenol) in 5 mL of methanol with 2 mol % of catalyst in a 25
mL Schlenk flask under argon atmosphere. Diazo compound added at
°C followed by warming to rt. Isolated product yield. We observed
trace amount of methanol O−H inserted product. We observed 10%
of unidentified product.
N3 110.2(3), P2−Cu1−N2 106.7(2), P2−Cu1−N3 118.3(3), N2−
Cu1−N3 92.0(4).
b
0
c
We started our investigation on catalytic carbene insertion into
the N−H bond with 2-aminophenol and α-phenyl diazoacetate
in DCM at rt with 2 mol % of complex 1 as a catalyst (Scheme 2).
The reaction was completed in 5 h and given N−H-inserted
product in 67% isolated yield along with carbene-dimerized
product.
with 1,2-bis(diphenylphosphino)ethane(dppe) we observed
5
3% of N−H-inserted product and 6% of O−H-inserted product
in 12 h (Table 1, entry 4), and in the case of 1,10-phenanthroline
with Cu(I) salt we observed 48% of N−H-inserted product, 11%
of O−H-inserted product, and 10% of unidentified products
Scheme 2. Copper-Catalyzed Chemoselective N−H Insertion
of α-Phenyl Diazoacetate into 2-Aminophenol
(
Table 1, entry 3). In the case of simple [(CH CN) Cu]ClO
3 4 4
salt and complex of 1,10-phenanthroline we observed a trace
amount of methanol O−H inserted product. This results clearly
revealed that the chemoselective N−H insertion over O−H
insertion occurs mainly because of catalyst 1.
These results further motivated us to explore the substrate
scope for this reaction. In order to understand the substrate
scope of our reaction and catalyst 1, first a wide range of α-aryl
diazoacetate compounds was explored with 2-aminophenols
Evidence for the selective carbene insertion into the N−H
1
bond was confirmed by H NMR with the appearance of a new
(
Table 2). All of the α-aryl diazoacetate compounds smoothly
underwent a selective N−H insertion reaction to afford the
singlet at 5.07 ppm for N-acetyl methine hydrogens, and in the
C NMR, a peak was observed at 61.6 ppm for N-acetyl tertiary
1
3
carbon. In the IR spectrum, bands were observed at 3323 and
Table 2. Copper(I) Complex Catalyzed Chemoselective N−H
Insertion of α-Aryl Diazoacetate into 2-Aminophenol
−1
3394 cm , which can be attributed to the stretching modes of
N−H and O−H bonds, respectively. Surprisingly, we have not
observed any O−H inserted product. This result clearly revealed
that the ligand plays the crucial role for selective carbene
insertion only into N−H bond. Nevertheless, relatively more
nucleophilicity of amine nitrogen over −OH cannot be ignored.
This result prompted us to optimize the reaction conditions that
would minimize dimerization of diazo and maximize the selective
N−H insertion. In order to identify the best solvent for this
reaction, we have screened some of the commonly used organic
solvents. We observed a best yield of 83% in methanol (Table S1,
entry 5 (Supporting Information)) at rt with 2 mol % of copper
catalyst 1. We have not observed any competitive products of
carbene inserted into the methanol −OH bond or aminophenol
a
R1
Et
b
entry
Ar
time (h)
3
yield (%)
1
2
Ph
Ph
Ph
6
5
6
5
5
5
4
5
4
5
a
b
c
d
e
f
83
81
90
76
78
82
76
78
80
71
i
Pr
3
Bn
Et
Et
Et
Et
Et
Et
Et
4
o-ClC H4
6
5
m-ClC H4
6
−OH bond.
6
p-ClC H4
6
In order to understand the role of catalyst 1, we have examined
various Cu(I) sources as catalysts for carbene insertion into the
7
p-BrC H4
g
h
i
6
8
o-OMeC H4
6
N−H bond, and the results are given in Table 1. With a simple
9
p-OMeC H4
6
[
(CH CN) Cu]ClO salt, we observed 56% of N−H-inserted
3
4
4
10
o-OMe, p-OMeC H3
j
6
product and 8% O−H-inserted product of 2-aminophenol
(
a
Table 1, entry 1), and when we used phosphine ligands we
All the reactions are carried out with 0.5 mmol (with respect to 2-
aminophenol) in 5 mL methanol with 2 mol % of catalyst in a 25 mL
Schlenk flask under argon atmosphere. Isolated product yield.
observed a longer reaction time. With triphenylphosphine we
observed 18% of N−H-inserted product in 8 h (Table 1, entry 2),
b
B
DOI: 10.1021/acs.orglett.5b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
corresponding hydroxy-functionalized α-amino esters, more
interestingly all the reactions given good to excellent yield
Scheme 3. Copper-Catalyzed Chemoselective N−H Insertion
of α-Aryl Diazoacetate into Different Aminophenols
(
71−90%). The electronic effects on the aryl ring of α-aryl
diazoacetate were also examined (Table 2, entries 6, 7, and 9),
and the electronic effects of diazo compounds marginally
reflected on the yield and reaction times. Among the α-aryl
diazoacetates, benzyl 2-diazo-2-phenylacetate (Table 2, entry 3)
gave the highest yield 90% and ethyl 2-diazo-2-(3,4-
dimethoxyphenyl)acetate (Table 2, entry 10) gave the lowest
yield 71% with 2-aminophenol.
The results of the selective carbene insertion into the N−H
bond of 2-aminophenol turned our interest toward conducting
similar reactions with 3- and 4-aminophenols with different α-
aryl diazoacetates. Both 3- and 4-aminophenols smoothly
underwent selective carbene insertion into the N−H bond
with a wide range of α-aryl diazoacetate compounds to afford the
corresponding hydroxy-functionalized α-amino esters (Tables
S3 and S4).
Unlike 2-aminophenol, 3- and 4-aminophenols have signifi-
cant electronic effects on the reaction of α-aryl diazoacetate. In
the case of 3-aminophenol, increasing the electron density on the
aryl ring causes a decrease in the yield and decreasing the electron
density on the aryl ring produced more yield (Table S3, entries 6,
7, and 9); the rate of reaction is relatively faster with electron-
donating groups on the aryl part of α-aryl diazoacetates. We
observed the highest yield with o- and p-Cl-substituted α-aryl
diazoacetates (Table S3, entries 4 and 6) and the lowest yield
with o-OMe-substituted α-aryl diazoacetates (Table S3, entry 8).
On the other hand, in case of 4-aminophenol, increasing electron
density on aryl ring decreased the yield, and decreasing electron
density on aryl ring offered relatively more yield (Table S4, entry
6
, 7 and 9). We observed more yield (85% and 86%) with o-OMe
and m,p-OMe substituents on aryl part of α-aryldiazoacetates
Table S4, entry 8 and 10) and lowest yield was observed with α-
(
phenyldiazoacetates (Table S4, entry 1).
In order to understand the substrate scope of our catalyst 1 for
the chemoselective carbene insertion into the N−H bond, we
investigated variety of aminophenols having various functional
groups. All the aminophenols smoothly underwent selective
carbene insertion (Scheme 3) and offered corresponding
hydroxy functionalized α-amino esters in good yield.
In order to gain more evidence for chemoselective carbene
insertion into the N−H bond, one of the products (6f) was
subjected to the single-crystal XRD studies, and the molecular
solid-state structure clearly revealed that the carbene from α-aryl
diazoacetates inserted into the N−H bond of aminophenol and
not into the −OH bond (Figure 2).
In summary, a novel air-stable well-defined copper(I) complex
was synthesized and characterized using standard spectroscopic
methods. Complex 1 promotes highly chemoselective insertion
of carbenes generated from α-aryl diazoesters into the N−H
bond over the O−H bond of various aminophenols under mild
reaction conditions. In order to demonstrate the scope of the
reaction, we screened a large number of aminophenols and α-aryl
diazoesters and found good to excellent yields for 42 examples.
We have examined similar reactions with different Cu(I) sources
to understand the role of catalyst 1. For other Cu(I) sources, the
selectivity for the formation of N−H-inserted product decreased
when compared to the selectivity observed with catalyst 1.
Further investigations in this line are in progress in our
laboratory.
Figure 2. Molecular structure of ethyl 2-((3-hydroxy-4-methylphenyl)-
amino)-2-phenylacetate (6f); thermal ellipsoids are set at 50%
probability. Hydrogen atoms are omitted for clarity.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01776.
X-ray cyrstallographic data (CIF)
Optimization, procedures, characterization data, and
NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.5b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
1
(
079−3081. (d) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl.
994, 33, 1797−1815.
AUTHOR INFORMATION
■
Corresponding Author
14) (a) Saha, B.; Ghatak, T.; Sinha, A.; Rahaman, S. M. W.; Bera, J. K.
Organometallics 2011, 30, 2051−2058. (b) Sinha, A.; Daw, P.; Rahaman,
*
E-mail: siva.che@pondiuni.edu.in. Tel: +91 413 2654709. Fax:
S. M. W.; Saha, B.; Bera, J. K. J. Organomet. Chem. 2011, 696, 1248−
+
91 413 2655987.
1
257. (c) Ho, C.-M.; Zhang, J.-L.; Zhou, C.-Y.; Chan, O.-Y.; Yan, J. J.;
Notes
Zhang, F.-Y.; Huang, J.-S.; Che, C.-M. J. Am. Chem. Soc. 2010, 132,
886−1894. (d) Deng, Q.-H.; Xu, H.-W.; Yuen, A. W.-H.; Xu, Z.-J.; Che,
1
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
C.S. gratefully acknowledges the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for financial
support (No. 01(2535)/11/EMR-II) and Viswanathula Ganesh,
Department of Chemistry, Pondicherry University, for solving
the crystal data. K.R. gratefully acknowledges the University
Grants commission (UGC) for a Junior Research Fellowship.
We thank the Central Instrumentation Facility, Pondicherry
University, for NMR spectra and DST-FIST for the single-crystal
X-ray diffraction facility and ESI-MS.
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