2-catalyzed directed N -Boc amidation of arenes "on water"

Article abstract of DOI:10.1021/acs.orglett.5b00392

Rhodium(III) catalysis "on water" is effective for directed C-H amidation of arenes. The catalytic process is promoted by OH groups present on the hydrophobic water surface and is inefficient in all (most) common organic solvents investigated so far. In the presence of easily prepared tert-butyl 2,4-dinitrophenoxycarbamate, a new and stable nitrene source, the "on water" reaction can efficiently provide the desired N-Boc-aminated products with good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.5b00392

Letter
pubs.acs.org/OrgLett
[RhCp*Cl2]2‑Catalyzed Directed N‑Boc Amidation of Arenes “on
Water”
Md Ashif Ali,§ Xiayin Yao,§ Hao Sun, and Hongjian Lu*
The Institute of Chemistry & BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, P. R. China
S
* Supporting Information
ABSTRACT: Rhodium(III) catalysis “on water” is effective
for directed C−H amidation of arenes. The catalytic process is
promoted by OH groups present on the hydrophobic water
surface and is inefficient in all (most) common organic
solvents investigated so far. In the presence of easily prepared
tert-butyl 2,4-dinitrophenoxycarbamate, a new and stable
nitrene source, the “on water” reaction can efficiently provide
the desired N-Boc-aminated products with good functional
group tolerance.
ater is the most ubiquitous solvent in biological systems,
and being abundant, nontoxic, nonflammable, and
compounds.9 As a part of our ongoing research on C−H
amination reactions,10 herein we report the first Rh(III)-
catalyzed, directed sp2 C−H activation/C−N bond formation
“on water” under neutral and nonoxidative conditions. This
process uses the easily accessible and bench-stable tert-butyl 2,4-
dinitrophenoxycarbamate (2)11 as a nitrene source. Water plays a
unique role, including two key functions: promoting the C−H
activation and assisting the absorption of the acidic side products.
The removal of the acidic side products and activation of metal
catalyst are generally achieved by adding bases and silver salts as
additives in organic solvents.9,12
We commenced our investigation by the reaction of 2-
phenylpyridine (1a) and the nitrene source 2 in the presence of 4
mol % of [RhCp*Cl2]2 “on water” at 60 °C and found that the
reaction proceeded smoothly to provide the desired ortho N-Boc-
aminated product (3a) with 88% conversion (82% isolated yield,
Table 1, entry 1). It should be noted that the reaction provided
70% conversion after only 10 min of reaction time (entry 2). In
the presence of a decreased amount of catalyst, a longer reaction
time was required to achieve acceptable levels of conversion
(entries 3 and 4). Additives such as AgSbF6 (entry 5) and
NaHCO3 (entry 6) failed to increase the yield. The rhodium(III)
catalyst was found to be ineffective for C−H bond amidation in
common organic solvents such as ClCH2CH2Cl, toluene,
CH3CN, THF, DMSO, i-PrOH, hexane, and DMF (entries 7−
14). In all these cases, the observed conversions were less than
11%. Additionally, the reactions with a catalytic or excess amount
of water as an additive in organic solvents failed (entries 15−18).
Finally, the reaction attempted without solvent was also
inefficient (entry 19).
W
environmentally benign, it could be regarded as the solvent of
Nature.1 In comparison with common organic solvents, the
unique and unusual physical and chemical properties of water,
such as amphiphilicity and hydrogen-bonding capability, can
deliberately influence the selectivity and reactivity of chemicals.2
Although the role of water is often unclear, many explanations,
such as stabilization of transition states by hydrophobic
hydration,3a−d hydrogen bonding,3e,f or hydrophobic interac-
tions3g and high cohesive energy density of water,3h are available
to explain enhanced rates of reaction in aqueous media. Despite
limited aqueous solubility of organic reactants, water has been
widely used as a solvent in organic reactions such as pericyclic
reactions, multicomponent reactions, Wittig reaction, and olefin
metathesis.1 Aqueous heterogeneous reactions have been
reinvestigated since Sharpless and co-workers reported a number
of “on water” reactions.4 It has been postulated that the
hydrophobic surface structures of water contain “dangling OH
groups” (OH groups which are not involved in intermolecular
hydrogen bonding) at the reactant−water interfaces5−7 and
stabilize the transition states by hydrogen-bonding interactions
to accelerate reaction rates.4a,b,5
In recent years, direct metal-catalyzed C−H functionalization
using water as a solvent has emerged as a research field of
immense interest.1f,8 The difficulties associated with such
reactions are the stability of the metal catalysts and ligands in
water. Metal catalysts may form complexes with water molecules,
and ligands such as phosphines are not tolerated in water.1f
Therefore, the scope for selection of suitable reactants and
catalysts is limited.1f Despite these challenges, metal-catalyzed
C−H activation/C−C, C−halogen, or C−O bond formation
methods have been developed for use in aqueous systems.8
However, C−H activation/C−N bond formation protocols with
water as a solvent have not been developed so far, even though it
is one of most efficient methods for the preparation of aminated
With these optimized conditions, we explored the substrate
scope for the C−H amidation “on water” (Scheme 1). Various
Received: February 6, 2015
Published: March 6, 2015
© 2015 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst loading (mol %)
additive
solvent
H2O
time
3 h
conv (%)
1
4
4
2
1
4
4
4
4
4
4
4
4
88 (82)
70
2
H2O
10 min
16 h
3
H2O
83
4
H2O
16 h
65
5
AgSbF6 (8 mol %)
H2O
3 h
85
6
NaHCO3(1.0 equiv)
H2O
3 h
3 h
3 h
3 h
3 h
3 h
90
c
7−12
13
organic
hexane
DMF
<5
8
14
11
d
15−17
18
H2O
ClCH2CH2Cl
iPrOH
<5
8
H2O (10 equiv)
19
16 h
25
a
b
1a (0.15 mmol), 2 (0.18 mmol), [RhCp*CI2]2 (4 mol %), and additive in solvent (1 mL). Conversion was calculated based on crude 1H NMR;
c
d
isolated yield in parentheses. ClCH2CH2Cl, PhMe, CH3CN, THF, DMSO, or iPrOH was used as solvent. 0.2, 1.0, or 10 equiv of H2O was used as
additive.
a,b
pyridylnaphthalene and 2-vinylpyridine could also be converted
to the desired products 3n and 3o, respectively. Similarly,
substrates bearing pyridine ring substituents such as fluoro,
methyl, and ester also gave the N-Boc-aminated products (3p−t)
in good yield. Furthermore, substrates with directing groups
other than pyridine, such as 1-phenyl-1H-pyrazole, were
tolerated to give the desired product (3u) in good yield, and 2-
phenylpyrimidine provided both the mono- and di-N-Boc-amino
products 3v and 3v′ in a 64:36 ratio, respectively.
Scheme 1. Substrate Scope
Inspired by the high selectivity and functional group tolerance
of this reaction, we further intended to examine some bioactive
substrates such as 6-arylpurinyl nucleosides which are known for
their anti-HCV, antimycobacterial, and cytostatic activities.13
The reaction proceeded smoothly with such substrates,
providing the mono-N-Boc-amino products in good yield.
Functional groups such as hydroxyl, phosphate ester, and
amino (3w−z) were also well tolerated.
To understand the unique role of water, we performed a series
of parallel experiments “on water” and in 1,2-dichloroethane
(ClCH2CH2Cl) (Scheme 2). The five-membered rhodocyclic
compound (4) can be prepared in 50% yield “on water” (eq 1)
and was able to catalyze the C−H amidation efficiently “on
water” (eq 5), while in the case of ClCH2CH2Cl no product
formation was observed (eq 2). This observation suggests that
a
1 (0.2 mmol), 2 (0.24 mmol), [RhCp*Cl2]2 (4 mol %), and H2O (1
b
c
mL) were stirred at 60 °C for 16 h. Isolated yield. Reaction time 1 h.
d
1 (0.15 mmol), 2 (0.30 mmol), [RhCp*Cl2]2 (4 mol %), and H2O (1
e
mL) were stirred at 60 °C for 24 h. The reaction was performed at 80
°C with 8 mol % of catalyst and 3.0 equiv of starting material 2.
Scheme 2. Reactions “on Water” or in ClCH2CH2Cl
substrates with substituents in the 2-phenyl ring (1b−m) readily
underwent reaction with the nitrene source 2 to give the desired
products in good to high yield. For example, meta-substituted 2-
phenylpyridines which contain functional groups commonly
used in organic synthesis, such as aldehyde, primary alcohol, O-
Tf, primary amide, and ester, were also converted to the desired
products (3d−h) with good yield. Furthermore, substrates
containing a Boc-protected amino acid ester (3i) and a weak N−
O bond (3j) were also tolerated, suggesting that the reaction
conditions are mild and highly selective. Likewise, compounds
with ortho- and para-substituents in the phenyl ring were
successfully N-Boc aminated (3k−m). Substrates such as 2-
a
b
Reaction time 12 h. Additional NaHCO3 (1.0 equiv) was used.
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Letter
complex 4 is involved in the catalytic cycle and is generated
through C−H activation with the assistance of water, but the
organic solvent ClCH2CH2Cl failed to assist the process. Next,
we treated complex 4 “on water” with 1.2 equiv of the nitrene
source 2 at 60 °C for 3 h and observed 43% formation of desired
product 3a “on water” but, surprisingly, 99% in ClCH2CH2Cl
(eqs 3 and 4). The higher yield obtained in ClCH2CH2Cl than
“on water” may possibly be due to the side product 2,4-
dinitrophenol, which could act as an acid (pKa = 4.09).14 In this
regard, 2,4-dinitrophenol may provide a proton to release the
product from the rhodium complex intermediate (see complex 8
in Figure 2B) in ClCH2CH2Cl.9j,q The higher conversion
achieved in the catalytic reaction (eq 5) than in the
stoichiometric reaction (eq 3) suggests that the proton in the
H-transfer step of the catalytic reaction probably comes from 2-
phenylpyridine 1a9o rather than 2,4-dinitrophenol (Figure 2B).
Meanwhile, less than 50% conversion even with a longer reaction
time (eqs 6 and 7) in ClCH2CH2Cl indicates that half of 1a may
act as a base. The reaction performed in the presence of 1 equiv of
base (NaHCO3) in ClCH2CH2Cl (eq 8) provided 83% of the
desired product, while the same reaction “on water” gave a yield
similar to that in the absence of any base (Scheme 2, eq 5). This is
because in ClCH2CH2Cl the pyridine functional group of the
product 3a cannot act as a base, possibly due to an intramolecular
H-bonding interaction with the amide group. Intermolecular H-
bonding between water and the amide group of product 3a helps
to regenerate the starting material 1a from [1a·H]+ “on water”
(Figure 1). Therefore, water has been shown to play two key
roles, promoting the formation of the active species 4 and
activating the product 3a to serve as a base.
molecular competition reaction of 1a-d1 with rhodocycle 4 or
[RhCp*Cl2]2 as catalyst (eqs 11 and 12), the DKIE of 3.8 and
3.5, respectively, were observed after consideration of the effect
of the catalyst (five-membered rhodocycle 4, 4 mol %, which
could form 4% of 3a directly). We have also observed the DKIE
of 2.6 for parallel reactions (see the Supporting Information for
details). This suggests that the C−H activation step is possibly
one of the rate-limiting steps,15 and the complex 4 is involved in
the catalytic cycle. The conversion was higher with 4 mol % of
species 4 than with 4 mol % of [RhCp*Cl2]2 (equal to 8 mol %
mono rhodium catalyst), possibly due to the comparatively slow
formation of rhodocycle 4 from [RhCp*Cl2]2 under these
reaction conditions (eqs 11 and 12). A DKIE of 4.0 for the
formation of species 4 was also obtained (eq 13).
To understand such unusual activation of [RhCp*Cl2]2 “on
water”, we tested whether or not the water can activate the
catalyst under homogeneous conditions, but the results were
negative (Table 1, entries 15−18). Hydrophobic water surfaces
have been reported to contain 25% dangling OH groups
protruding into the hydrophobic phase,5−7 and this finding has
been used to explain the enhanced rate of “on water”
reactions.4a,5 Considering this phenomenon as an explanation
of our observations, we suggest that dangling OH groups
protruding into the hydrophobic phase activate [RhCp*Cl2]2 by
hydrogen bonding and, thus, support the formation of five-
membered rhodocyclic complex 4 which is the active species9h
(Figure 2A). The complex 4 may convert to 5 by removal of a Cl−
Figure 1. Water-promoted regeneration of 1a from [1a·H]+.
Next, we investigated the H/D scrambling and deuterium
kinetic isotope effects (DKIE) (Scheme 3). A negligible amount
of H/D exchange was observed in the presence or absence of the
nitrene source 2 (eqs 9 and 10), indicating that the amidation
process is faster compared to H/D exchange. In an intra-
Scheme 3. Kinetic Experiments
Figure 2. Possible Reaction Pathway.
ion by H2O. Complex 5 then may react with 1a and the nitrene
source 2 to generate the intermediate 6, which then may be
converted to 7 via valence expansion of Rh(III) to Rh(V) (Figure
2B). The intermediate 7 may be converted to 8 by stepwise
nitrenoid transfer,16 which was observed in the ESI mass
spectrum (see the Supporting Information). The intermediate 8
may coordinate with 1a to give the intermediate 9, which then
may undergo C−H activation and then rearrange to intermediate
10 through a transition state B. The intermediate 10 will react
with water to give the product 3a and the intermediate 5, thus
completing the catalytic cycle. The pyridinium ion [1a·H]+
generated during the formation of intermediate 6 regenerates
a
Using D2O/H2O (0.5 mL/0.5 mL) as the solvent at 60 °C for 10
min.
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Letter
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1a in a reaction promoted by water in the presence of the product
3a as shown in Figure 1, and in this way, the reaction can proceed
“on water” without any additional base.
In conclusion, we report the first C−H amidation “on water”
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data for the products, and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
* E-mail: hongjianlu@nju.edu.cn
Author Contributions
§M.A.A. and X.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support by the National Natural
Science Foundation of China (21332005, 21472085, 21402087),
Qing Lan Project, and the Natural Science Foundation of Jiangsu
Province (BK20131267). We thank our colleague Haifei Zhang
for assisting with HRMS analysis.
(10) Selected example: Lu, H. J.; Li, C. Q.; Jiang, H. L.; Lizardi, C. L.;
Zhang, X. P. Angew. Chem., Int. Ed. 2014, 53, 7028.
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