Cu(I)-mediated reductive amination of boronic acids with nitroso aromatics.

Article abstract of DOI:10.1021/ol048982q

[reaction: see text] A mild method for the reductive amination of aryl boronic acids with nitroso aromatic compounds is reported. This C-N bond formation is mediated by a stoichiometric amount of CuCl as both a catalyst and a reducing agent. Alternatively, 10% Cu(I)-3-methylsalicylate (CuMeSal) catalyzes the same reaction in the presence of either ascorbic acid or hydroquinone as the terminal reducing agent. Diarylamines bearing a variety of functional groups can be obtained in good yields.

Full text of DOI:10.1021/ol048982q

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ORGANIC
LETTERS
2004
Vol. 6, No. 15
2631-2634
Cu(I)-Mediated Reductive Amination of
Boronic Acids with Nitroso Aromatics
Ying Yu, Jiri Srogl, and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe,
Atlanta, Georgia 30322
chemLL1@emory.edu
Received June 2, 2004
ABSTRACT
A mild method for the reductive amination of aryl boronic acids with nitroso aromatic compounds is reported. This C−N bond formation is
mediated by a stoichiometric amount of CuCl as both a catalyst and a reducing agent. Alternatively, 10% Cu(I)-3-methylsalicylate (CuMeSal)
catalyzes the same reaction in the presence of either ascorbic acid or hydroquinone as the terminal reducing agent. Diarylamines bearing a
variety of functional groups can be obtained in good yields.
Oxidative addition of a lower-valent transition metal catalyst
LnM to a heteroatom-heteroatom bond X-Y generates a
species LnM(X)Y capable of further functionalization in a
variety of ways (i.e., Scheme 1). Transformations that
logues with unsaturated organics such as alkynes,1 alkenes,2
CO,3 and isonitriles.4 Sulfenamides have been shown to react
with CO,5 and O-sulfonylated oximes and related derivatives6
as well as N-haloamines7 participate in palladium-catalyzed
aza-Heck-like reactions that are presumably initiated by
oxidative addition to an N-X bond.
Less common are nominal cross-coupling reactions in
which the LnM(X)Y intermediate is intercepted with an
organometallic carbon nucleophile to provide, after reductive
elimination, products with newly generated carbon-hetero-
atom bonds (lower cycle of Scheme 1). In this way Narasaka
Scheme 1
(1) Kuniyasu, H.; Ogawa, A.; Miyazaki, S.; Ryu, I.; Kambe, N.; Sonoda,
N. J. Am. Chem. Soc. 1991, 113, 9796. Han, L.-B.; Tanaka, M. J. Am.
Chem. Soc. 1998, 120, 8249.
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Soc. 1999, 121, 482.
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(4) Kuniyasu, H.; Sugoh, K.; Su, M. S.; Kurosawa, H. J. Am. Chem.
Soc. 1997, 119, 4669.
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Kurosawa, H. J. Org. Chem. 1999, 64, 7305.
(6) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45; 2001, 526. Kitamura,
M.; Zaman, S.; Narasaka, K. Synlett 2001, 974. Narasaka, K. Pure Appl.
Chem. 2002, 74, 143. Kitamura, M; Narasaka, K. Chem. Rec. 2002, 2, 268.
Chiba, S.; Kitamura, M.; Saku, O.; Narasaka, K. Bull. Chem. Soc. Jpn.
2004, 77, 785.
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G.; Kalsow, S.; Go¨ttlich, R. Eur. J. Org. Chem. 2002, 1848. Noack, M.;
Go¨ttlich, Eur. J. Org. Chem. 2002, 3171.
proceed via the upper cycle of Scheme 1 are increasingly
common and include the reactions of disulfides and ana-
10.1021/ol048982q CCC: $27.50 © 2004 American Chemical Society
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and co-workers relied on cleavage of the O-N bond of
oxime derivatives to establish a copper-catalyzed amination
of cuprates and Grignard reagents.8
N,O-diacyl-N-benzenesulfohydroxamic acid) generated only
modest results.14 Attention was then transferred from hy-
droxylamine to nitroso derivatives15 with the objective of
gaining additional insight into the reaction chemistry of
boronic acids with N-O systems, in general.
Further development of this tactic as a general synthetic
sequence could provide a useful complement to the various
palladium- and copper-catalyzed cross-coupling reactions that
have revolutionized the way in which synthetic chemists
generate carbon-heteroatom bonds. These cross-coupling
reactions currently fall into two broad categories: the
anaerobic, metal-catalyzed cross-coupling of N, O, S, and P
nucleophiles with organic halides or their equivalents9 and
complementary “oxidative” aminations, amidations, alkoxy-
lations, aryloxylations, and thiations of boronic acids medi-
ated by Cu(II).10,11 Guided by the cross-coupling concept
depicted in the bottom cycle of Scheme 1, we have initiated
an exploration of metal-catalyzed reactions of various
heteroatom-heteroatom reactants with mild reaction partners
such as boronic acids to seek out new and mild approaches
to C-heteroatom bonded systems. We have previously
demonstrated that boronic acids easily couple with N-
thioimide derivatives to give thioethers under neutral condi-
tions in the presence of a Cu(I) catalyst.12 This Letter
describes a second new method uncovered as part of that
study.
Heating 2-nitrosotoluene with a stoichiometric amount of
Cu(I)-thiophene-2-carboxylate (CuTC)16 and a slight molar
excess of phenylboronic acid at 55 °C in THF for 16 h gave
2-methyldiphenylamine in 61% isolated yield.17 Control
experiments demonstrated the requirement for a stoichio-
metric amount of Cu(I), suggesting that Cu(I) functioned as
both a catalyst for the transformation as well as a stoichio-
metric reducing agent for the requisite N-O bond generated
during the reaction.18 Premixing the nitroso aromatic com-
pound with a stoichiometric amount of the Cu(I) salt prior
to addition of the boronic acid greatly diminished the
formation of undesired side products derived from copper-
mediated oxidative homocoupling and protodeborylation of
the boronic acid.19 Among the different Cu(I) compounds
assayed (Cu(I) thiophene-2-carboxylate, CuTC;16 Cu(I) 3-m-
ethylsalicylate, CuMeSal;20 CuI; CuCl; CuOAc; (CuSO3-
CF3)2‚C6H5CH3; and (CuSO3CF3)2‚C6H6) CuCl gave the best
results and DMF was the preferred solvent of those probed
(toluene, THF, DMF, DMA, NMP, and pyridine).
Following the cross-coupling concept depicted in the lower
cycle of Scheme 1, the reaction of hydroxylamine derivatives
with boronic acids13 could provide a means of generalizing
the “oxidative” amination of boronic acids10 by using an
oxidized form of the amine coupling partner rather than an
external oxidant.11 However, exploratory metal-catalyzed
reactions of boronic acids with various hydroxylamine
derivatives (O-aryl-N-acyl hydroxylamines acids, O-alkyl-
N-acylhydroxylamines, N,O-diacyl-N-phenylhydroxylamine,
As depicted in Table 1 a variety of unsymmetrical
diarylamines bearing different functional groups were easily
prepared using the optimized conditions.21 Boronic acids
bearing both electron-donating and electron-withdrawing
groups led to good yields of the products (entries 2, 3, and
6), and functional groups such as aldehyde and ester (entries
4, 5, 7, and 9) were compatible with the almost neutral
reaction conditions.
(14) Both hydroxylamine and hydrazine derivatives are known to
participate in palladium- or copper-catalyzed carbon-heteroatom bond
formation without cleavage of the heteroatom-heteroatom bond: Petrassi,
H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3, 139. Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. Kwong, F. Y.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. Kabalka, G. W.;
Guchhait, S. K. Org. Lett. 2003, 5, 4129. Lim, Y.-K.; Lee, K.-S.; Cho,
C.-G. Org. Lett. 2003, 5, 979.
(15) Arylnitroso compounds are easily generated from nitroaromatics and
have been widely used in organic synthesis. See in ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol 6, Chapter 1.4 by Askani, R.; Taber, D. F.; Yogt, P. F.; Miller, M. J.
Tetrahedron 1998, 54, 1317.
(16) Allred, G.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(17) A related preparation of diarylamines from arylmagnesium reagents
and nitroarenes has been described: Sapountzis, I.; Knochel, P. J. Am. Chem.
Soc. 2002, 124, 9390.
(18) The use of substoichiometric quantities of Cu(I) did not lead to the
formation of the corresponding N,N-diarylhydroxylamine.
(8) Tsutsui, H.; Narasaka, K. Chem. Lett. 2001, 526. Tsutsui, H.; Hayashi,
Y.; Narasaka, K. Chem. Lett. 1997, 317.
(9) Leading references: Hartwig, J. F. In Modern Amination Methods;
Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany, 2000. Hartwig, J. F. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley-Interscience: New York, 2002; p 1051. Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. Zim, D.; Buchwald, S.
L. Org. Lett. 2003, 5, 2413. Kwong, F. Y.; Buchwald, S. L. Org. Lett.
2003, 5, 793. Gujadhur, R.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001,
3, 4315. Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002,
4, 2803. Ma, D.; Qian, C.; Zhang, H. Org. Lett. 2003, 5, 2453. Ma, D.;
Qian, C. Org. Lett. 2003, 5, 3799. Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Parisi, L. M. Org. Lett. 2002, 4, 4719. Montchamp, J.-L.; Dummond, Y.
R. J. Am. Chem. Soc. 2001, 123, 510.
(10) Leading references: Chan, D. M. T.; Monaco, K. L.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933. 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. Finet, J. P.; Fedorov, A. Y.; Combes, S.; Boyer, G.
Curr. Org. Chem. 2002, 6, 597. Lam, P. Y. S.; Vincent, G.; Bonne, D.;
Clark, C. G. Tetrahedron Lett. 2003, 44, 4927. Chan, D. M. T.; Monaco,
K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett.
2003, 44, 3863. Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs,
A. P. Tetrahedron Lett. 2003, 44, 1691.
(19) The efficiency of the protodeborylation of boronic acids with CuTC
varies with the reaction conditions. For reference, see: Srogl, J.; Liebeskind,
L. S. J. Am. Chem. Soc. 2000, 122, 11260.
(20) See Supporting Information for Savarin, C.; Srogl, J.; Liebeskind,
L. S. Org. Lett. 2001, 3 (1), 91.
(11) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233. Collman, J. P.;
Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528. Collman,
J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem. 2001, 66, 7892.
Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415. Antilla, J. C.; Buchwald, S. L. Org Lett.
2001, 3, 2077. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397.
(12) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309.
(13) The amination of organoboron reagents with hydroxylamine O-
sulfonic acid is also known, but a metal-catalyzed amination of boron
reagents with hydroxylamine derivatives would greatly expand the scope
of this chemistry. See Encyclopedia of Reagents for Organic Synthesis, 1st
ed.; Paquette, L. A., Ed.; John Wiley & Sons: New York, 1995; Vol. 4.
(21) Typical Experimental Procedure. 2-Nitrosotoluene (38 mg, 0.3
mmol) and CuCl (30 mg, 0.3 mmol) were placed in a Schlenk tube that
was flushed with argon. Dry DMF (8 mL) was added, and the dark brown
mixture was stirred at 55 °C for 40 min. Phenylboronic acid (41 mg, 0.33
mmol) was dissolved in DMF (3 mL) and added to the reaction tube. The
mixture was heated at 55 °C for 16 h, cooled, and then partitioned between
Et2O (20 mL) and 1 M NH4OH (20 mL). The aqueous layer was extracted
with Et2O (2 × 10 mL), and the combined organic layers were dried with
MgSO4. The oily residue obtained after evaporation was subjected to
preparative plate silica gel chromatography (gradient of hexanes/EtOAc)
giving 2-methyldiphenylamine (46 mg, 83%) as brown oil. Full character-
ization details are available in Supporting Information.
2632
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the oxidant. However, when a mixture of PhNH2, 2-nitro-
sotoluene, phenylboronic acid, 10% CuMeSal, and 1 equiv
of ascorbic acid in DMF was heated at 55 °C for 16 h, only
2-methyldiphenylamine was observed. The absence of di-
phenylamine in the reaction mixture argues against the
intervention of free anilines in the N-arylation process. In
any event the formation of the undesired aniline and azoxy
byproducts was greatly minimized by adding the ascorbic
acid to the reaction mixture portion-wise. Under optimal
reaction conditions a DMF solution of the nitrosoarene, the
boronic acid, and 10% CuMeSal was heated at 55 °C for 2
h, then 0.5 equiv of ascorbic acid was added followed by a
second 0.5 equiv 1 h later. After a total of 4 h a clear yellow
solution was obtained that was subjected to workup. Some
diarylamines that were prepared in this fashion are sum-
marized in Table 2.24
Table 1. CuCl-Mediated Amination of Arylboronic Acids with
Nitroso Aromatic Compoundsa
entry
Ar
o-tol
Ar′
product yield (%)b
1
2
3
4
5
6
7
8
9
Ph
83
81
70
72
81
61
78
64
70
o-tol
Ph
4-MeOC6H4
4-C6H4CF3
Ph
Ph
4-C6H4CO2Me
3-C6H4CHO
Ph
2-C6H4F
Ph
Ph
4-Cl-o-tol
4-MeO-2-C6H3CHO
2-dibenzofuranyl
4-C6H4CO2Me
a Dry DMF (8 mL) was added to a reaction vessel holding a mixture of
the nitroso aromatic (0.3 mmol) and CuCl (0.3 mmol), which was then
heated to 55 °C for 30-40 min. The aryl boronic acid (0.33 mmol) was
dissolved in 3 mL of DMF and then added, and the reaction mixture was
stirred at 55 °C for another 16 h. b Isolated yields, average of two runs.
Table 2. CuMeSal-Catalyzed Amination of Arylboronic Acids
with Nitroso Aromatic Compounds Using Ascorbic Acid (AA)
and Hydroquinone as Reducing Agents
In the reductive amination of the boronic acid with the
nitrosoarene, 1 equiv of a reducing agent is required in order
to complete the transformation from a putative N-O
intermediate to the observed diarylamine product. The role
of reducing agent is served by a stoichiometric amount of
CuCl, although control experiments demonstrated that an
additional equivalent of the boronic acid could also function
as the terminal reducing agent (forming an equivalent of
phenol in the process). Thus, in the presence of 20 mol %
CuTC, 2 equiv of phenylboronic acid and 1 equiv of
2-nitrosotoluene gave 60% of 2-methyldiphenylamine.
To render the reaction catalytic in copper without sacrific-
ing an equivalent of the boronic acid, the reaction was
explored in the presence of various terminal reducing agents.
In fact, heating 1 equiv of ascorbic acid,22 phenylboronic
acid, and 2-nitrosotoluene in the presence of 10% Cu(I)-3-
methylsalicylate (CuMeSal) gave 2-methyldiphenylamine in
55% yield along with lesser amounts of 2-methylaniline and
2,2′-dimethylazoxybenzene as byproducts. A control experi-
ment revealed formation of aniline by an ascorbic acid
mediated reduction of the nitrosoarene, a process that
presumably takes place via the arylhydroxylamine. The
reduction is accelerated in the presence of a catalytic amount
of a Cu(I) source, such as CuMeSal. Formation of the
azoxybenzene is then easily rationalized by condensation
of the nitrosoarene with the transiently generated aryl-
hydroxylamine.23
product yield (%)a
entry
Ar
Ar′
I
II
1
2
3
4
5
6
o-tol
Ph
Ph
Ph
Ph
Ph
87
84
79
78
75
80
80
65
68
65
74
4-C6H4CF3
4-C6H4CO2Me
2-C6H4F
3-C6H4CHO
2-dibenzofuranyl
Ph
a Isolated yield from the average of two runs.
Compared to the use of a stoichiometric amount of CuCl
(Table 1), the ascorbic acid/catalytic Cu(I) system gave
generally better results and possessed satisfactory functional
group compatibility. Hydroquinone also served as an alternate
and very mild terminal reducing agent (Table 2) but gave
slightly lower yields of the product diarylamines relative to
ascorbic acid. However, the low acidity of hydroquinone
(24) Typical Experimental Procedure. Using ascorbic acid: dry DMF
(8 mL) was added to an argon-flushed Schlenk tube containing 2-nitroso-
toluene (38 mg, 0.3 mmol), phenylboronic acid (41 mg, 0.33 mmol), and
CuMeSal (6 mg, 0.03 mmol). The mixture was stirred at 55 °C for 1 h, and
then ascorbic acid (30 mg, 0.15 mmol) in 1 mL DMF was added. One
hour later an identical portion of ascorbic acid (30 mg, 0.15 mmol) was
added. The mixture was heated at 55 °C for 4 h, cooled to room temperature,
and partitioned between Et2O (20 mL) and aqueous NH4OH (20 mL, 1
M). The aqueous layer was extracted with Et2O (2 × 10 mL), and the
combined organic layers were dried with MgSO4. The residue after
evaporation was subjected to preparative plate silica chromatography
(gradient of hexanes/EtOAc) giving the desired product (48 mg, 87%) as a
brown oil. A similar reaction using hydroquinone added in one portion gave
the desired product in 80% yield (44 mg). Full characterization details are
available in Supporting Information.
Reduction of the nitrosoarene to the aniline suggested a
mechanistic pathway to the N,N-diarylamine in which a
portion of the nitrosoarene is first reduced to the aniline,
which then undergoes a copper-mediated, oxidative coupling
with the boronic acid10 using the remaining nitrosoarene as
(22) Ascorbic acid (vitamin C) functions as a weakly acidic and mild
reducing agent in biological systems. For a review, see: Padh, H. Nutr.
ReV. 1991, 49, 65.
(23) Zuman, P.; Shah, B. Chem. ReV. 1994, 94, 1621.
Org. Lett., Vol. 6, No. 15, 2004
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helped minimize the formation of the undesired azoxy and
aniline side products. As a result, there was no need for slow
addition of hydroquinone and all reagents could be heated
together to obtain satisfactory yields of the desired amination
products.
of an N,N-diarylhydroxylamine. This intermediate would
suffer an internal redox generating the diarylamine and an
oxidized Cu species. Under conditions catalytic in copper,
the oxidized Cu species would be reduced by ascorbic acid27
or hydroquinone to a catalytically active form of Cu(I).
In summary, a mild reductive amination of arylboronic
acids with nitrosoarenes has been developed. The reaction
is mediated either by a stoichiometric quantity of CuCl or
with catalytic Cu(I) 3-methylsalicylate in the presence of
ascorbic acid or hydroquinone as terminal reducing agents.
The method provides an interesting synthetic complement
to existing protocols for C-N bond formation and begins
to expand our understanding of carbon-heteroatom cross-
coupling using heteroatom-heteroatom bonded species. For
example, it may prove feasible to couple nitroaromatics with
boronic acids by pairing the chemistry depicted in this Letter
with a mild in situ reduction of a nitroaromatic to the
corresponding nitrosoarene.28 This and related transforma-
tions based on metal-mediated heteroatom-heteroatom
cleavages are under study.
A suggested mechanism for the copper-mediated reductive
amination of arylboronic acids with nitrosoarenes is depicted
in Scheme 2. Side-on complexation of Cu(I) with the nitroso
Scheme 2
Acknowledgment. The National Institutes of General
Medical Sciences, DHHS supported this investigation through
grant GM066153.
moiety25 generates a formal Cu(III) intermediate that would
be susceptible to transmetalation by the boronic acid.26
Reductive elimination would then generate a Cu(I) alkoxide
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Otsuka, S.; Aotani, Y.; Tatsuno, Y.; Yoshida, T. Inorg. Chem. 1976,
15, 656. Ittel, S. D. Inorg. Chem. 1977, 16, 2589. Lee, J.; Chen, L.; West,
A. H.; Richter-Addo, G. B. Chem. ReV. 2002, 102, 1019.
(26) For transmetalation between zinc and copper leading to effective
electrophilic amination, see: Erdik, E.; Daskapan, T. Synth. Commun. 1999,
29, 3989.
OL048982Q
(27) Bose, S.; Nair, N. J. Indian Chem. Soc. 1974, 51, 505. Yano, Y.;
Takano, S.; Kato. Y.; Tagaki, W. J. Chem. Soc., Perkin Trans. 2, 1979, 9,
1227.
(28) For comparison, see footnote 17.
2634
Org. Lett., Vol. 6, No. 15, 2004