Arenes to anilines and aryl ethers by sequential iridium-catalyzed borylation and copper-catalyzed coupling

Article abstract of DOI:10.1021/ol062902w

(Chemical Equation Presented) N-Alkyl- and N-arylanilines were synthesized from arenes by a two-step sequence of iridium-catalyzed borylation and copper-catalyzed coupling with amines. Diaryl ethers were obtained by a related sequence of arene borylation, followed by coupling with phenols. In particular, 3,5-disubstituted arylamines and aryl ethers were prepared by initiating this sequence with meta-substituted arenes.

Full text of DOI:10.1021/ol062902w

ORGANIC
LETTERS
2007
Vol. 9, No. 5
761-764
Arenes to Anilines and Aryl Ethers by
Sequential Iridium-Catalyzed Borylation
and Copper-Catalyzed Coupling
C. Christoph Tzschucke, Jaclyn M. Murphy, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520, and Department of Chemistry,
UniVersity of Illinois, 600 South Matthews AVenue, Urbana, Illinois 61801
jhartwig@uiuc.edu
Received November 30, 2006
ABSTRACT
N-Alkyl- and N-arylanilines were synthesized from arenes by a two-step sequence of iridium-catalyzed borylation and copper-catalyzed coupling
with amines. Diaryl ethers were obtained by a related sequence of arene borylation, followed by coupling with phenols. In particular, 3,5-
disubstituted arylamines and aryl ethers were prepared by initiating this sequence with meta-substituted arenes.
The iridium-catalyzed borylation of arenes1-8 is a one-step
method to generate aryl boronates, which are convenient
synthetic intermediates. The most active catalyst (referred
to herein as the IMH catalyst) for the conversion of arenes
to arylboronic esters is generated from di-tert-butylbipyridine
and [Ir(COD)(OMe)]2 and was developed jointly by the
Ishiyama and Miyaura group and our group.1a,2-4
The direct conversion of arenes to arylamines is limited.9
We envisioned a route from arenes to arylamines by the
combination of C-H borylation of arenes and conversion
of the arylboronic ester to the arylamine. Chan and Lam first
reported the copper-mediated conversion of arylboronic acids
to arylamines,10,11 and numerous systems for this process
have now been reported.10-14 A similar route to biaryl ethers
by the borylation of arenes, followed by copper-mediated
coupling of arylboronic acids with phenols,10b,15 can be
envisioned.
(1) (a) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N.
R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390. (b) Chotana, G. A.;
Rak, M. A.; Smith, M. R., III. J. Am. Chem. Soc. 2005, 127, 10539.
(2) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem.,
Int. Ed. 2002, 41, 3056.
(3) (a) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem.
Commun. 2003, 2003, 2924. (b) Boller, T. M.; Murphy, J. M.; Hapke, M.;
Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
14263.
(4) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N.
AdV. Synth. Catal. 2003, 345, 1103.
(5) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M.
R., III. Science 2002, 295, 305.
Although many methods for the functionalization of arenes
by electrophilic aromatic substitution are known, and some
of these electrophilic substitutions generate precursors to
(9) (a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006,
128, 9048. (b) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 14560. (c) Hoffmann, N.; Muhler, M. Catal. Lett. 2005,
103, 155. (d) Yamamoto, M.; Matsubara, S. Chem. Lett. 2007, 36, 172. (e)
Yu, T.; Hu, C.; Wang, W. Chem. Lett. 2005, 34, 406.
(6) Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III. J. Am.
Chem. Soc. 2003, 125, 7792.
(7) Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr.; Smith, M. R., III.
Org. Lett. 2006, 8, 1407.
(10) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters,
M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. (b)
Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron
Lett. 1998, 39, 2933.
(8) Shi, F.; Smith, M. R., III; Maleczka, R. E., Jr. Org. Lett. 2006, 8,
1411.
(11) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, Germany, 2005; pp 205-240.
10.1021/ol062902w CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/03/2007

arylamines, access to 1,3,5-trisubstituted arenes remains a
synthetic challenge. Many substituents direct electrophilic
aromatic substitution to the ortho and para positions, and
most meta-directing substituents deactivate arenes toward this
process. Thus, 1,3,5-trisubstituted arenes containing three
different substituents are often difficult to access.
Table 1. Coupling of Alkylamines with Arylboronate Esters
Generated by Ir-Catalyzed Arene Borylation
The selectivity of arene borylation typically complements
the selectivity of electrophilic aromatic substitutions. Because
the position of the boronate group in the product is dictated
more by steric effects than by electronic effects, the C-H
activation occurs faster at positions meta and para to existing
substituents than at positions ortho to them. As a result,
reactions of meta-disubstituted arenes lead to 3,5-disubsti-
tuted arylboronates.1,5,6,16 This feature has been exploited to
synthesize 3,5-disubstituted phenols by the borylation of
arenes with the IMH catalyst and subsequent oxidation6,7 and
has also been used to synthesize 1,3,5-substituted arylamino
boronates by catalytic borylation of halogenated arenes using
the IMH catalyst, followed by Pd-catalyzed amination of the
halides.7,8 The products of the C-H borylation have also
been used in situ for Suzuki-Miyaura cross coupling.4,5,17
Here, we report the conversion of arenes to arylamines
and aryl ethers by a sequence of arene borylation, followed
by copper-mediated amination and etherification. This
sequence forms 3,5-disubstituted arylamines and aryl ethers
from commercially available meta-substituted arenes. The
synthesis of arylamines by this method complements the
classical synthesis of arylamines by nitration, reduction and
alkylation, or the more recently developed synthesis of
arylamines by the coupling of amines with haloarenes that
would have been generated by electrophilic aromatic halo-
genation.
Scheme 1 and Table 1 show the general strategy by which
3,5-disubstituted boronic esters were generated for conversion
to 1,3,5-substituted arylamines. The arenes were first con-
verted to the arylboronic ester by reaction with bispinaco-
latodiboron (B2pin2), 0.025 mol % of [(COD)Ir(OMe)]2, and
0.05 mol % of 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) in
cyclohexane (Scheme 1).2,4,18 The arylboronate esters were
Scheme 1. Borylation of Arenes for Conversion to
Arylaminesa
a Isolated yields after column chromatography based on the amount of
ArBpin in the crude arylboronate ester, as judged by NMR spectroscopy
of the crude material from the C-H borylation process. b 1 equiv
Cu(OAc)2‚H2O was used.
formed in high yields with this low loading of 0.05 mol %
of the iridium. These reactions were conducted with arenes
containing halogens, carbomethoxy, trifluoromethyl, and
alkoxo groups.
a Yields given are for crude product recovered after the removal
of volatile materials under vacuum.
762
Org. Lett., Vol. 9, No. 5, 2007

Scheme 2. Arylboronic Acids by C-H Borylation and
Table 2. Coupling of Arylamines with Arylboronic Acids
Generated by Ir-Catalyzed Arene Borylation and Oxidative
Hydrolysis
Oxidative Hydrolysis with Aqueous NaIO4
After this C-H bond functionalization process, the solvent
was removed from the reaction mixture, and the crude
arylboronic esters were converted to arylamines by a copper-
mediated process (Table 1, top). This conversion of aryl-
boronates esters to arylamines was not straightforward by
existing literature.
Arylboronic esters are much less reactive than arylboronic
acids toward the copper-mediated amination and etherifica-
tion chemistry. For example, the Cu-mediated oxidative
coupling of aryl boronic acids with 10 mol % of Cu(OAc)2‚
H2O, 20 mol % of DMAP, and molecular sieves in methylene
chloride reported by Batey14 does not occur with arylboronic
esters. Nevertheless, we found that reactions of the crude
arylboronates with 2 equiv of alkylamine and 1 equiv of
potassium fluoride in the presence of 10-20 mol % of
Cu(OAc)2‚H2O and powdered molecular sieves in acetonitrile
in an oxygen atmosphere occurred to form the desired
arylamine at 80 °C. Potassium fluoride might be aiding in
the transmetalation of the aryl group from boron to copper,
and molecular sieves were added to remove water liberated
from the copper precursor. The arylalkylamines were then
isolated by column chromatography.
A summary of the formation of arylamines from crude
boronic esters, which were generated from meta-substituted
arenes, is provided in Table 1. Reactions of primary amines
occurred with the arylboronic esters to generate 3,5-disub-
stituted N-alkylanilines. The reactions occurred with a linear
and a cyclic primary alkylamine, as well as a protected
aminoaldehyde. Although the yields were modest in some
cases, reactions of the more electron-poor arylboronic esters
usually occurred in acceptable yields.
In contrast to the reactions of primary alkylamines, the
reactions of secondary alkylamines formed the coupled
(12) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K.
M.; Chan, D. M. T.; Combs, A. Synlett 2000, 5, 674. (b) Lam, P. Y. S.;
Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001,
42, 3415. (c) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs,
A. P. Tetrahedron Lett. 2003, 44, 1691. (d) Chan, D. M. T.; Monaco, K.
L.; Li, R. H.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett.
2003, 44, 3863. (e) Thomas, A. W.; Ley, S. V. Angew. Chem., Int. Ed.
2003, 115, 5558.
a Isolated yields after column chromatography based on arylamine. b 30
mol % Cu(OAc)2 and 60 mol % decanoic acid were used.
(13) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(14) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397.
(15) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(16) (a) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science
2000, 287, 1995. (b) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. J. Am.
Chem. Soc. 2000, 122, 12868. (c) Tse, M. K.; Cho, J.-Y.; Smith, M. R.,
III. Org. Lett. 2001, 3, 2831.
(17) Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A.
S.; Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angew. Chem., Int. Ed.
2006, 45, 489.
(18) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura,
N. AdV. Synth. Catal. 2003, 345, 1103.
product in low yields. Even the use of stoichiometric amounts
of Cu(OAc)2‚H2O generated the dialkylaniline products in
modest yields. Further, the coupling of the arylboronic esters
with arylamines did not occur under Batey’s conditions, our
modified reaction conditions, or Buchwald’s conditions for
the coupling of arylboronic acids with arylamines in the
presence of copper and myristic acid.13
Considering these limitations, we used a reaction sequence
described in detail in the accompanying paper in which
Org. Lett., Vol. 9, No. 5, 2007
763

The copper-mediated conversion of arylboronic acids to
aryl ethers10,15 also does not occur with pinacol arylboronic
esters. For example, reactions of the arylboronic esters with
p-tert-butylphenol in the presence of catalytic or stoichio-
metric amounts of Cu(OAc)2 did not form the desired biaryl
ether. Thus, our studies on the conversions of arenes to aryl
ethers focused on reactions of the arylboronic acids generated
by C-H borylation and oxidative hydrolysis of the resulting
pinacol boronic ester.
Table 3. Coupling of Phenols with Arylboronic Acids
Generated by Ir-Catalyzed Arene Borylation and Oxidative
Hydrolysis
These reactions of the boronic acids are summarized in
Table 3. The crude arylboronic acids reacted with phenols
to form biaryl ethers. The coupling of an ortho and para-
substituted phenol occurred with the crude 3,5-disubstituted
arylboronic acids in the presence of 1 equiv of Cu(OAc)2, 5
equiv of triethylamine, and molecular sieves in CH2Cl2 at
room temperature, as described by Evans.15 Reaction of the
ortho-substituted phenol and the electron-poor cyano-
substituted phenol occurred in modest yield, as is typical
for these reactions to form biaryl ethers.20 However, reactions
involving the electron-neutral and p-chloro-substituted phe-
nols occurred in good yield.
In conclusion, a sequence of Ir-catalyzed borylation and
Cu-mediated amination or etherification provides a method
to convert arenes to arylamines and aryl ethers. In particular,
this method allows the synthesis of 3,5-disubstituted aryl-
amines and aryl ethers from meta-substituted arenes. Al-
though the synthesis of N-alkylanilines was accomplished
by coupling of primary alkylamines with the arylboronates
generated by the C-H activation process, the synthesis of
diarylamines and diaryl ethers relied on the accompanying
conversion of arenes to arylboronic acids by a sequence of
C-H activation and oxidative hydrolysis. Thus, C-H
activation, oxidative hydrolysis, and copper-mediated cou-
pling generates 3,5-disubstituted diarylamines and diaryl
ethers.
a Isolated yields after column chromatography.
arylboronic acids are generated by a combination of C-H
borylation and oxidative hydrolysis (Scheme 2).19 The crude
aryl boronic acids formed by this procedure and isolated by
extraction into EtOAc underwent copper-catalyzed oxidative
coupling with arylamines to form diarylamines. These
reactions were conducted with 10 mol % of anhydrous
Cu(OAc)2, 20 mol % of decanoic acid, and 1 equiv of 2,6-
lutidine in toluene under air, as described by Buchwald.13
After chromatography, the diarylamines were obtained in
high yields (Table 2).
Acknowledgment. C.C.T. thanks the German academic
exchange service (DAAD) for a postdoctoral fellowship. We
thank the NSF for support of this work. We thank Frontier
Science for a gift of bis-pinacolatodiboron.
Supporting Information Available: Experimental pro-
cedures and spectral data for reaction products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062902W
(19) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9,
757.
(20) (a) Sawyer, J. S. Tetrahedron 2000, 56, 5045. (b) Ley, S.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
764
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