Practical catalytic method for synthesis of sterically hindered anilines

Article abstract of DOI:10.1039/c5cc03565a

A practical catalytic method for the synthesis of sterically hindered anilines is described. The amination of aryl and heteroaryl boronic esters is accomplished using a catalyst prepared in situ from commercially available and air-stable copper(i) triflat

Full text of DOI:10.1039/c5cc03565a

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ARTICLE
Practical Catalytic Method for Synthesis of Sterically Hindered
Anilines.
Melrose Mailig,a Richard P. Rucker,a and Gojko Lalic*a
Received 00th January 20xx,
Accepted 00th January 20xx
A practical catalytic method for the synthesis of sterically hindered anilines is described. The amination of aryl and heteroaryl
boronic esters is accomplished using a catalyst prepared in situ from commercially available and air-stable copper(I)triflate
and diphosphine ligand. For the first time, the method can be applied to the synthesis of both secondary and tertiary anilines
in the presence of a wide range of functional groups. Esters, aldehydes, alcohols, aryl halides, ketones, nitriles, and nitro
arenes are all compatible with the reaction conditions. Finally, even the most sterically hindered anilines can be successfully
prepared under mild reaction conditions. Overall, the new method addresses significant practical limitations of a
transformation previously developed in our lab, and provides a valuable complement to the existing methods for the
synthesis of anilines.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Aromatic and heteroaromatic amines have important synthesis of even the most sterically hindered anilines, such as
applications in medicinal chemistry and the pharmaceutical compound
3
.
industry.1, 2 As a result, several catalytic transformations have Unfortunately, several features of our method significantly
been developed to facilitate access to this important class of limited its practical utility: 1) The pre-catalyst, (CuOt-Bu)4, is
organic compounds. The most general and commonly used are hard to prepare,20 is extremely air sensitive, and has to be
copper-catalyzed Ullman3 and palladium-catalyzed Buchwald- handled in a glovebox; 2) The use of LiOt-Bu as a turnover
Hartwig4, 5 cross coupling reactions, which have an excellent reagent prevents the use of protic functional groups in either
scope and provide access to a wide range of anilines from coupling partner; 3) The method can be used only in the
readily available starting materials.6-10 However, some synthesis of N,N-dialkyl anilines, and the synthesis of N-alkyl
important challenges remain. The most notable one is the anilines is not possible. In this communication, we report a
synthesis of highly sterically hindered anilines, which are practical method for the synthesis of both secondary and
difficult to access using the common catalytic methods.11
There are very few methods useful for the synthesis of sterically limitations.
tertiary sterically hindered anilines that addresses all of these
Scheme 1. Synthesis of sterically hindered anilines.
hindered anilines. Knochel reported an oxidative coupling of
aryl Grignard reagents with amines, using a stoichiometric
amount of a copper salt and an oxidant.12 Sterically hindered
anilines can also be prepared in reactions of highly reactive
benzyne intermediates.13, 14 In a rare instance of a catalytic
method used in the synthesis of hindered anilines, Johnson
reported three examples of electrophilic amination of aryl zinc
reagents by hindered electrophiles15-18 This method requires
the use of a significant excess (>2 equiv) of an aryl lithium
reagent. Recently, we have reported a related catalytic method
for electrophilic amination of aryl and heteroaryl boronic esters
(Scheme 1).19 Our method avoids the use of highly reactive
intermediates, and allows the synthesis of a wide range of
functionalized anilines, including iodo, bromo, or nitro anilines.
Most importantly, our method proved to be well suited for the
In the reaction shown in Scheme 1, the choice of the catalyst
precursor was dictated by the turnover reagent. Previously, we
have shown that LiOt-Bu reacts with N,N-dialkyl-O-benzoyl
hydroxylamines at a significant rate in all but the highly
nonpolar solvents, such as isooctane.19 The low polarity of the
solvent, in turn, severely limits the choice of a precatalyst. We
found that in isooctane, (CuOt-Bu)4 is uniquely effective as a
precatalyst, although a small amount of toluene still had to be
used to facilitate the preparation of the active catalyst. Based
on this analysis of the problems associated with the reaction
a.Department of Chemistry, Unioversity of Washington, Seattle, WA 98195, USA
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: Characterization data for all
new compounds, experimental procedures. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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shown in Scheme 1, we focused on finding a new turnover The optimized reaction conditions proved to be quite general
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DOI: 10.1039/C5CC03565A
reagent.
and could be used to prepare a wide range of aryl and
heteroaryl anilines (Table 2). The reaction can be successfully
performed in the presence of esters, nitriles, aldehydes,
ketones, carbamates, iodo arenes, bromo arenes and nitro
Table 1. Catalytic amination of aryl boronic esters.
arenes. As demonstrated by the synthesis of compound 18
,
even protic functional groups are compatible with the reaction
conditions.
Table 2. Synthesis of tertiary amines.a
In a preliminary experiment, we found that CsF is compatible
with N,N-dialkyl-O-benzoylated-hydroxylamines in a wide range
of solvents, even at elevated temperatures. However, when CsF
was used instead of LiOt-Bu as a turnover reagent in the
reaction shown in Scheme 1, 72 h were required for complete
conversion.19 More importantly, no product formation occurred
in reactions with a significant number of substrates. As a result,
we decided to reinvestigate all aspects of the reaction and
explore the electrophilic amination of aryl boronic esters using
a wide range of copper precatalysts, in combination with a
number of phosphine ligands, in several organic solvents.
Through the standard optimization of the reaction parameters,
we found that the best results are obtained using a catalyst
prepared in situ from copper(I) triflate benzene complex and
Heteroaromatic boronic esters, such as pyrrole, thiophene,
pyrimidine, and pyridine boronic esters could also be
successfully used in the reaction. Finally, even the extremely
hindered anilines such as 19 are made in excellent yields and
under relatively mild reaction conditions. It is also worth
pointing out that the catalyst precursor, copper(I) triflate
benzene complex, is commercially available and sufficiently
ligand 4, in THF (Table 1).
During the reaction optimization we found that several other
copper(I) salts can also serve as a catalyst precursor, although
yields were generally lower. We also found that copper (II) salts
can be used as precursors in the presence of sodium ascorbate.
stable to be weighted in air. Similarly, ligand
4 is commercially
available and air stable. Overall, the reaction conditions
described in Table 2 are practical and can be applied to a wide
range of substrates.
We were especially interested in expanding the scope of this
reaction to the synthesis of N-alkyl anilines. In previous
attempts, using N-alkyl-O-benzoyl hydroxylamines as
electrophiles we never observed the formation of the desired
N-alkyl anilines; furthermore the reaction conditions described
in Table 1 proved equally ineffective in the synthesis of
secondary anilines.
Interestingly, with copper(II) precursors there was
a
considerable induction period, suggesting that the reduction of
copper(II) precursor may limit the overall rate of the reaction.
Diphosphine ligand
4 and Xantphos ligand gave comparable
results. However, other common bidentate phosphine ligands
with a smaller bite angle, gave inferior results. Finally, in
addition to THF, 2-Me-THF or 1,4-dioxane can also be used as a
solvent, while the other common organic solvents gave inferior
results.
2 | J. Name., 2012, 00, 1-3
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We identified the presence of acidic protons in both the Giri.21 As a result, we focused on the C-N bond forming step of
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DOI: 10.1039/C5CC03565A
electrophile and the desired N-alkyl aniline products as a the reaction.
Scheme 3. Proposed mechanism.
potential source of the problem. We further speculated that
deprotonation of either the electrophile or the product by an
aryl copper intermediate leads to the formation of a copper
anilide and results in inactivation of the catalyst. To provide
experimental evidence for this hypothesis, we exposed an
isolated copper aryl complex 25 to N-tert-butyl-O-benzoyl
hydroxylamine (Scheme 2). To our surprise, the stoichiometric
reaction resulted in a formation of the desired N-alkyl aniline in
excellent yield, indicating that the presence of acidic protons
does not affect the C-N bond-forming step of the catalytic
reaction.
Scheme 2. Stoichiometric synthesis of N-alkyl anilines.
We showed that copper(I) aryl complexes supported by
diphosphine ligands react with N,N-dialkyl-O-benzoyl
hydroxylamines at 65 °C, and within 0.5 hours produces the
expected aniline product in excellent yield (Scheme 3). The
reaction shown in Scheme 2 demonstrates that the same
stoichiometric reaction is feasible with N-alkyl-O-benzoyl
hydroxylamines.
Intrigued by the result of the stoichiometric experiment, we
decided to explore slow addition of the electrophile over the
course of the reaction. We found that by adding N-alkyl-O-
benzoyl hydroxylamine electrophiles to the reaction mixture
over three hours, we can accomplish the desired
transformation using the otherwise standard reaction
conditions described in Table 2.
Table 3. Synthesis of secondary amines.a
100
50
time (min)
0
0
50
100
150
Figure 1. Yield of the aniline product as a function of time. Reaction
conditions: 4-BrC6H4Bneop (1.2 equiv), i-Pr2NOBz (1.0 equiv), CuOTf
1/2C6H6 (2.5 mol %), 4 (3.5 mol %), CsF (3 equiv), 80 °C, THF.
We have also explored the kinetics of the reaction. Initially, we
monitored the change in the concentration of the product with
time until the full conversion of the electrophile was achieved.
Somewhat surprisingly, we found that the overall rate of the
reaction does not significantly change during the course of the
As shown in Table 3, a range of hindered N-alkyl anilines and reaction (Figure 1). Furthermore, we found that the initial rate
heteroanilines can be prepared using this procedure. Not of the reaction does not depend on the concentration of either
surprisingly, the transformation can still be performed in the the aryl boronic ester or the concentration of the electrophile.24
presence of sensitive functional groups, such as aryl iodides and These observations are all consistent with the rate of the
aldehydes.
reaction being limited by the low solubility of CsF in organic
We propose that the catalytic amination of boronic esters solvents. In this scenario, the turnover limiting step of the
proceeds according to the mechanism shown in Scheme 3. The catalytic cycle would be the formation of the copper fluoride
formation of the copper fluoride complex from various other intermediate 33, and the catalyst resting state would be the
copper salts in the presence of CsF or KF has been copper benzoate intermediate 35
demonstrated.21, 22 Similarly, transmetalation involving copper
.
fluoride complexes and organoboron compounds is well-
documented, most notably by Shibasaki23 and more recently by
Conclusions
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We have developed a practical method for the synthesis of 17 T. J. Barker and E. R. Jarvo, J. Am. Chem. Soc., 2009, 131
,
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DOI: 10.1039/C5CC03565A
highly sterically hindered anilines through electrophilic
15598-15599.
amination of aryl and heteroaryl boronic esters. The copper 18 C. Zhu, G. Li, D. H. Ess, J. R. Falck and L. Kürti, J. Am. Chem.
catalyst is prepared in situ from commercially available and air- Soc., 2012, 134, 18253-18256.
stable precursors. The method can be applied to the synthesis 19 R. P. Rucker, A. M. Whittaker, H. Dang and G. Lalic, Angew.
of both secondary and tertiary anilines, and is compatible with Chem. Int. Ed., 2012, 51, 3953-3956.
a wide range of functional groups, including carboalkoxy, 20 T. H. Lemmen, G. V. Goeden, J. C. Huffman, R. L. Geerts and K.
formyl, cyano, and hydroxyl. Furthermore, aryl iodides and aryl G. Caulton, Inorg. Chem., 1990, 29, 3680-3685.
bromides are also compatible with the reaction conditions, 21 S. K. Gurung, S. Thapa, A. Kafle, D. A. Dickie and R. Giri, Org.
making this method complementary to the other cross-coupling Lett., 2014, 16, 1264-1267.
reactions commonly used in the synthesis of anilines. Finally, 22 H. Dang, M. Mailig and G. Lalic, Angew. Chem. Int. Ed., 2014,
even the most sterically hindered anilines can be successfully 53, 6473-6476.
made under relatively mild reaction conditions. Overall, the 23 R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M. Kanai and M.
readily available catalyst precursors, mild reaction conditions Shibasaki, J. Am. Chem. Soc., 2006, 128, 7687-7691.
and exceptionally broad substrate scope make this method a 24 For a more detailed description of the results, see ESI.
valuable tool for the synthesis of sterically hindered anilines.
Acknowledgements
Financial support by NSF (NSF CAREER award #1254636) is
gratefully aknowledged.
Notes and references
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