Copper-catalyzed amination of arylboronates with N,N-dialkylhydroxylamines

Article abstract of DOI:10.1002/anie.201108773

A tolerant coupling: The title reaction has been developed to deliver arylamines (see scheme; Bz=benzoyl, dppbz=1,2-bis(diphenylphosphino)benzene). The catalysis is based on electrophilic, umpolung amination and enables the use of secondary acyclic amines. Various functional groups are tolerated, thus opening up a new substrate class for the Chan-Lam-type coupling.

Full text of DOI:10.1002/anie.201108773

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Angewandte
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DOI: 10.1002/anie.201108773
Synthetic Methods
Copper-Catalyzed Amination of Arylboronates with
N,N-Dialkylhydroxylamines**
Naoki Matsuda, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
À
Metal-mediated aromatic C N bond-forming reactions rank
as one of the most useful and important transformations in
organic synthesis because the resultant arylamine motifs are
prevalent in many natural products and pharmaceutical
(GC; Scheme 1). Some observations concerning optimization
studies are to be noted: other bases such as Cs2CO3, K3PO4,
and LiOH·OH2 largely led to a reduced yield; anhydrous
[Cu(OAc)2] and CuOAc showed similarly high performances,
so we employed [Cu(OAc)2·OH2] for the subsequent experi-
ments owing to its good tractability.[9]
targets.[1] Among them, the copper-promoted C N bond
À
formation of arylboronic acids with amines and amides
(Chan–Lam coupling) is quite attractive owing to some
benefits such as commercial availability, low toxicity, and
tractability associated with copper salts and organoboron
compounds.[2] Since the pioneering works in 1998,[3] a variety
of reaction systems have been widely explored, and now
catalytic variants are available. However, the coupling with
dialkylamines is often inefficienct. In particular, the amina-
tion with secondary acyclic alkylamines still remains a chal-
lenge.[4] Herein, we report a copper-catalyzed amination of
arylboronates with electrophilic aminating reagents,
hydroxylamines. The catalysis allows the coupling of arylbor-
ons with various alkylamines, particularly secondary acyclic
amines. In addition, by taking advantage of the high reactivity
of an organocopper intermediate towards hydroxylamines in
preference to aryl halides, the compatibility with aryl iodides
as well as bromides is also achieved. Although related
approaches are reported by Liebeskind and co-workers[5]
and Lei and co-workers,[6] they are limited to amidation and
imination.[7] Reported electrophilic amination reactions with
hydroxylamines are restricted to highly reactive and mois-
ture-sensitive organometallic reagents such as aryl Grignard
reagents and arylzincs. The boron-based reagent is a more
practical, easy-to-handle, and functional group tolerant alter-
native to the above organometallics.[8] Thus, the present
strategy complements the precedented work and provides
a new substrate class to the Chan–Lam-type coupling.
Scheme 1. Optimized reaction conditions for copper-catalyzed amina-
tion of phenylboronic acid neopentylglycol ester (1a) with O-benzoyl-
N,N-diethylhydroxylamine (2a).
Under the optimized reaction conditions (Scheme 1), we
examined the scope of the boronates 1 with O-benzoyl-N,N-
dibenzylhydroxylamine (2b) (Table 1). In addition to the
simple 1a (entry 1), arylboronates bearing not only electron-
donating groups (1b,c; entries 2 and 3) but also electron-
withdrawing groups (1d–f; entries 4–6) underwent the ami-
nation smoothly. Particularly notable is the fact that aryl–
halogen bonds including chloride, bromide, and iodide were
tolerated under the reaction conditions (entries 4–6). The
mildness of conditions accommodated methyl ester, phenyl
Table 1: Copper-catalyzed amination of various arylboronic acid neo-
pentylglycol esters 1 with O-benzoyl-N,N-dibenzylhydroxylamine (2b).[a]
In a typical experiment, treatment of phenylboronic acid
neopentylglycol ester (1a) with O-benzoyl-N,N-diethyl-
hydroxylamine (2a) in the presence of 10 mol% [Cu-
(OAc)2·OH2]/dppbz (dppbz = 1,2-bis(diphenylphosphino)-
benzene) and 2.0 equivalents of LiOtBu in THF at room
temperature afforded N,N-diethylaniline (3aa) in 71% yield
Entry
1 (Ar)
3, Yield [%][b]
1
2
3
4
5
6
7
8
1a (Ph)
3ab, 89
3bb, 72
3cb, 68
3 db, 93
3eb, 83
3 fb, 53
3gb, 77
3hb, 73
3ib, 81
3jb, 64
3kb, 76
3lb, 63
3mb, 87
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (4-ClC6H4)
1e (4-BrC6H4)
1 f (4-IC6H4)
1g (4-MeOCOC6H4)
1h (4-PhCOC6H4)
1i (4-CHOC6H4)
1j (2,4,6-Me3C6H2)
1k (1-naphthyl)
1l (2-thienyl)
[*] N. Matsuda, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry, Faculty of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
9
10
11
12
13
miura@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from the Ministry
of Education, Culture, Sports, Science, and Technology (Japan).
K.H. acknowledges Kansai Research Foundation for the Promotion
of Science.
1m (3-thienyl)
[a] Reaction conditions: [Cu(OAc)2·OH2] (0.025 mmol), dppbz
(0.025 mmol), LiOtBu (0.50 mmol), 1 (0.25 mmol), 2b (0.30 mmol),
THF (1.5 mL), N2, RT, 4 h. [b] Yield of the isolated product. Bn=benzyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108773.
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ketone, and aldehyde moieties (entries 7–9). The sterically
demanding mesityl- and 1-naphthylboronates (1j and 1k,
respectively) also furnished the corresponding anilines 3jb
and 3kb in synthetically useful yields (entries 10 and 11).
Furthermore, the electrophilic amination protocol could be
applied to the synthesis of heteroarylamines such as 2-thienyl-
and 3-thienylamines (3lb and 3mb, respectively; entries 12
and 13). Attempts to use alkylboronates such as butylboronic
acid neopentylglycol ester remained unsuccessful.
Next, the amination with an array of O-benzoylhydroxyl-
amines was carried out. To further demonstrate the halogen
compatibility of the process, the bromo- (1e) and iodo-
substituted (1 f) compounds were selected as the arylboronate
(Scheme 2). Acyclic amines bearing N,N-diethyl, N,N-diallyl,
À
Scheme 3. Iridium-catalyzed C H borylation/copper-catalyzed electro-
philic amination sequence.
tions. The amination reaction proceeded very smoothly to
furnish the corresponding aniline 4a in 83% yield based on
2b. With the same protocol, meta-dichlorobenzene was also
converted into 4b with good efficiency. In addition, a
[Ir(OMe)(cod)]2/P[3,5-(CF3)2C6H3]3-catalyzed ortho boryla-
tion[12] could be followed by the amination to furnish the
corresponding 1,2,3-trisubstituted aniline 4c. These examples
demonstrate that the sequential Ir/Cu process could give
a rapid and concise approach to anilines having electron-
deficient substituents. Moreover, the introduction of the
electrophilic amination reagent allows more sterically
demanding pinacol boronates to be adopted directly in the
Scheme 2. Copper-catalyzed amination of arylboronates 1e and 1 f
with various hydroxylamines 2 performed using the reaction conditions
from Table 1. Boc=tert-butoxycarbonyl.
À
C N bond formation at a synthetically useful level. This is
a significant advantage because the pinacol boronates tend to
be less reactive than the parent boronic acids and their
successful conversion is not trivial under the conventional
Chan–Lam coupling conditions.[13]
N-benzyl-N-methyl substituents were compatible under stan-
dard reaction conditions (3ea–ed and 3 fa). In particular, 3ec
and 3ed could enjoy additional structural elaboration after
appropriate removal of the allyl and benzyl groups.[10] The
reaction with cyclic systems was subsequently investigated.
The six-membered piperidine and morpholine derivatives
coupled with both 1e and 1 f effectively (3ef, eg and 3 ff, fg),
whereas the hydroxylpyrrolidine showed a somewhat lower
reactivity (3ee). The piperazine rings bearing a Boc group, as
well as the bicyclic tetrahydroisoquinoline derivative were
also compatible (3eh, ei and 3 fi).
To investigate whether the catalysis involves an aminyl
radical species (or its copper-coordinated form), we con-
ducted the aminaion with 2j containing a pendant olefinic
moiety [Eq. (1)]. If the radical process was operative, some
Our copper-catalyzed electrophilic amination could be
À
easily combined with the iridium-catalyzed direct C H
borylation of simple arenes (Scheme 3).[11] Namely, 1,3-
bis(trifluoromethyl)benzene was directly borylated with
pinB-Bpin using the [Ir(OMe)(cod)]2/dtbpy (dtbpy = 4,4’-
di(tert-butyl)-2,2’-bipyridine; cod = 1,5-cyclooctadiene) cata-
lyst, and the resulting mixture was then transferred into
a solution of O-benzoyl-N,N-dibenzylhydroxylamine (2b),
copper catalyst, and LiOtBu in THF without any purifica-
pyrrolidine-containing products would be formed through
a 5-exo cyclization.[14] However, the usual coupling product
3aj was obtained exclusively, thus excluding the radical
pathway. Further mechanistic studies were carried out with
the isolated MesCu complex 5.[15] A stoichiometric reaction of
5 with 2b in the presence of dppbz gave no detectable amount
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of 3jb [Eq. (2)]. Any additives such as LiOtBu, LiOAc,
from the reaction of 8 with the hydroxylamine 2, and the
monoarylcopper 7 is regenerated to complete the catalytic
cycle. The proposed diarylcuprate 8 can account for the result
in Equation (3); a heterodiarylcuprate formed in situ trans-
fers one of its aryl groups with moderate selectivity in favor of
the formation of 3eb, probably owing to steric factors. A
stoichiometric reaction with Mes2CuLi prepared from CuCl
and 2.0 equivalents of MesLi also support the hypothesis
[Eq. (5)]. The postulated reaction order of the copper
B(OMe)3, or combinations thereof did not form 3jb at all. In
contrast, upon treatment of 5 with 1e as an additional aryl
source, the corresponding anilines 3jb and 3eb were pro-
duced with a quantitative combined yield in a ratio of 39:61
[Eq. (3)]. Moreover, the mesitylcopper 5 catalyzed the
amination of 1j with 2b very efficiently [Eq. (4)]. The
complex (transmetalation then interaction with the electro-
philic amination reagent) contrasts with the precedented
works, in which an alternative is suggested.[5,6] The difference
might arise from the lower electrophilicity of the hydroxyl-
amines 2 than hydroxylamides or chloroamides.[18] Addition-
ally notable is that under the current system the monoar-
ylcopper species does not couple with the hydroxylamine 2,
whereas [(phen)CuC6F5] does couple very smoothly even
without any additives in our previous work.[19] These results
indicate that the reactivity of organocopper complexes
toward electrophilic amination reagents depends highly
upon the steric and electronic nature of both their anionic
and neutral ancillary ligands, and thus provide some benefi-
À
cial insights into the electrophilic, umpolung C N bond-
forming process by copper catalysts.
phenomenon suggests that a monoarylcopper like 5 could
be included in the catalytic cycle, but an active species
In conclusion, we have developed a copper-catalyzed
amination of arylboronates with O-benzoylhydroxylamines
bearing alkyl groups. The copper-based electrophilic, umpo-
lung amination approach enables the use of secondary acyclic
amines, which is a relatively difficult substrate class for the
conventional Chan–Lam couplings. Moreover, the catalysis
accommodates a diverse set of functional groups including
chlorides, bromides, and iodides as well as aldehydes, ketones,
and esters. The reaction system may complements previous
work and provides a new substrate class for the Chan–Lam
coupling. Investigations into the improvement of the catalytic
À
responsible for the C N bond formation can be a diaryl-
cuprate rather than monoaryl species.
Based on the above considerations and literature infor-
mation, we propose the mechanism for the amination as
illustrated in Scheme 4. There is initial reduction of CuII into
CuI and ligand exchange with LiOtBu to generate the
CuOtBu species 6. Subsequent transmetalation with the
neopentylglycol boronate 1 furnishes the monoarylcopper
7.[16] A second equivalent of boronate 1 then reacts with 7 with
the aid of additional LiOtBu to generate a more reactive ate-
type diarylcuprate 8.[17] The aniline product 3 would the result
À
turnover towards a more practical C N coupling, a more
detailed mechanism,[20] and additional developments of
related electrophilic amination reactions are now in progress.
Experimental Section
Copper-catalyzed amination of phenylboronic acid neopentylglycol
ester (1a) with O-benzoyl-N,N-dibenzylhydroxylamine (2b) (Table 1,
entry 1): [Cu(OAc)2·OH2] (5.0 mg, 0.025 mmol), 1,2-bis(diphenyl-
phosphino)benzene (dppbz, 11 mg, 0.025 mmol), and LiOtBu (40 mg,
0.50 mmol) were placed into a 20 mL two-necked reaction flask,
which was filled with nitrogen by using the standard Schlenk
technique. THF (0.50 mL) was then added to the flask, and the
suspension was stirred for 15 min at ambient temperature. Finally,
a solution of phenylboronic acid neopentylglycol ester (1a, 48 mg,
0.25 mmol), O-benzoyl-N,N-dibenzylhydroxylamine (2b, 95 mg,
Scheme 4. Plausible reaction mechanism.
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0.30 mmol), and 1-methylnaphthalene (ca. 25 mg, internal standard)
in THF (1.0 mL) was added dropwise. The solution was stirred at
ambient temperature for additional 4 h. The resulting mixture was
quenched with water. An aqueous solution of 4m HCl (60 mL) was
added to the mixture. The aqueous layer was washed four times with
Et2O, neutralized with 6m NaOH aq. (40 mL), and then extracted
four times with Et2O. The combined organic layers was dried over
sodium sulfate. Concentration in vacuo and subsequent purification
by column chromatography on silica gel with n-hexane/ethyl acetate/
Et3N (40:1:0.25, v/v/v) as an eluent gave N,N-dibenzylaniline (3ab,
61 mg, 0.22 mmol) in 89% yield.
123, 8475; Angew. Chem. Int. Ed. 2011, 50, 8325; also see: h) E.
Erdik, M. Ay, Chem. Rev. 1989, 89, 1947; i) T. J. Barker, E. R.
Jarbo, Synthesis 2011, 3954.
[9] See the Supporting Information for more detailed optimization
studies.
[10] a) S. Jaime-Figueroa, Y. Liu, J. M. Muchowski, D. G. Putman,
Tetrahedron Lett. 1998, 39, 1313; b) V. Cadierno, S. E. Garcꢀa-
Garrido, J. Gimeno, N. Nebra, Chem. Commun. 2005, 4086; c) J.-
Y. Wang, D.-X. Wang, Q.-Y. Zheng, Z.-T. Huang, M.-X. Wang, J.
Org. Chem. 2007, 72, 2040.
[11] a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi,
J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390; b) J. M. Murphy,
X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129, 15434.
[12] T. Ishiyama, H. Isou, T. Kikuchi, N. Miyaura, Chem. Commun.
2010, 46, 159.
Received: December 13, 2011
Revised: January 13, 2012
Published online: March 1, 2012
[13] Limited examples: a) C. S. Guy, T. C. Jones, Synlett 2009, 2253;
b) A. S. Voisin, A. Bouillon, J.-C. Lancelot, A. Lesnard, S. Rault,
Tetrahedron 2006, 62, 5350; c) C. C. Tzschucke, J. M. Murphy,
J. F. Hartwig, Org. Lett. 2007, 9, 761.
[14] a) T. Tsuda, T. Yazawa, K. Watanabe, T. Fujii, T. Saegusa, J. Org.
Chem. 1981, 46, 192; b) P. Leoni, M. Pasquali, C. A. Ghilardi, J.
Chem. Soc. Chem. Commun. 1983, 240; c) E. M. Meyer, S.
Gambarotta, C. Floriani, A. Chiesi-Villa, C. Guastini, Organo-
metallics 1989, 8, 1067.
[15] a) M. Noack, R. Gçttlich, Chem. Commun. 2002, 536; also see:
b) T. Tsuritani, H. Shinokubo, K. Oshima, Org. Lett. 2001, 3,
2709; c) T. Tsuritani, H. Shinokubo, K. Oshima, J. Org. Chem.
2003, 68, 3246.
Keywords: amination · anilines · boron · copper ·
synthetic methods
.
[1] a) R. Hili, A. K. Yudin, Nat. Chem. Biol. 2006, 2, 284; b) Amino
Group Chemistry, From Synthesis to the Life Sciences (Ed.: A.
Ricci), Wiley-VCH, Weinheim, 2007.
[2] Reviews: a) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115,
5558; Angew. Chem. Int. Ed. 2003, 42, 5400; b) D. M. T. Chan,
P. Y. S. Lam, in Boronic Acids (Ed.: D. G. Hall), Wiley-VCH,
Weinheim, 2005, chap. 5, p. 205; c) J. X. Qiao, P. Y. S. Lam,
Synthesis 2011, 829.
[16] For transmetallation between copper salts and neopentylglycol
boronates by the action of metal alkoxides, see: a) H. Ohmiya,
N. Yokokawa, M. Sawamura, Org. Lett. 2010, 12, 2438; b) R.
Shintani, K. Takatsu, T. Hayashi, Chem. Commun. 2010, 46,
6822; c) C.-T. Yang, Z.-Q. Zhang, Y.-C. Liu, L. Liu, Angew.
Chem. 2011, 123, 3990; Angew. Chem. Int. Ed. 2011, 50, 3904;
d) K. Takatsu, R. Shintani, T. Hayashi, Angew. Chem. 2011, 123,
5662; Angew. Chem. Int. Ed. 2011, 50, 5548; e) R. Shintani, K.
Takatsu, T. Hayashi, Angew. Chem. 2011, 123, 8815; Angew.
Chem. Int. Ed. 2011, 50, 8656; f) F. Yang, Z. Xu, Z. Wang, Z. Yu,
R. Wang, Chem. Eur. J. 2011, 17, 6321.
[17] a) J. K. Kochi, Organometallic Mechanisms and Catalysis, Aca-
demic Press, New York, 1978, p. 372; b) J. M. Klunder, G. H.
Posner, Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, 207; c) J.-E. Bꢁck-
vall, E. S. M. Persson, A. Bombrun, J. Org. Chem. 1994, 59, 4126;
d) E. Nakamura, S. Mori, K. Morokuma, J. Am. Chem. Soc.
1998, 120, 8273; e) E. R. Bartholomew, S. H. Bertz, S. Cope, M.
Murphy, C. A. Ogle, J. Am. Chem. Soc. 2008, 130, 11244.
[18] To get additional insights into an interaction between a CuI salt
and hydroxylamines, BzONBn2 (2b) was exposed to a THF
solution of 1.0 equiv of CuOtBu, which was freshly generated
from MesCu (5) and tBuOH. However, no reaction took place,
and 2b was quantitatively recovered intact (see below). Thus,
our postulated reaction order (transmetalation then interaction
with hydroxylamines) could be more plausible. P. O. Ogua-
dinma, F. Schaper, Can. J. Chem. 2010, 88, 472.
[3] a) D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters,
Tetrahedron Lett. 1998, 39, 2933; b) P. Y. S. Lam, C. G. Clark, S.
Saubern, J. Adams, M. P. Winters, D. M. T. Chan, A. Combs,
Tetrahedron Lett. 1998, 39, 2941; around the same time, Evans
À
reported a relevant C O bond-forming reaction: c) D. A. Evans,
J. L. Katz, T. R. West, Tetrahedron Lett. 1998, 39, 2937.
[4] Limited successful examples: a) J. C. Antilla, S. L. Buchwald,
Org. Lett. 2001, 3, 2077; b) A. P. Combs, S. Tadesse, M. Rafalski,
T. S. Haque, P. Y. S. Lam, J. Comb. Chem. 2002, 4, 179; c) X.-Q.
Yu, Y. Yamamoto, N. Miyaura, Chem. Asian J. 2008, 3, 1517.
[5] a) S. Liu, Y. Yu, L. S. Liebeskind, Org. Lett. 2007, 9, 1947; b) S.
Liu, L. S. Liebeskind, J. Am. Chem. Soc. 2008, 130, 6918; c) Z.
Zhang, Y. Yu, L. S. Liebeskind, Org. Lett. 2008, 10, 3005.
[6] C. He, C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li, A. Lei, Angew.
Chem. 2008, 120, 6514; Angew. Chem. Int. Ed. 2008, 47, 6414.
[7] Lei attempted the amination of phenylboronic acid with N,N-
dibutylchloroamine, but the yield was low (11%); see Ref. [6].
À
For relevant halogen-compatible C N formations based on
palladium catalysts, see: a) H.-Y. Thu, W.-Y. Yu, C.-M. Che, J.
Am. Chem. Soc. 2006, 128, 9048; b) A. A. Jordan-Hore, C. C. C.
Johansson, M. Gulias, E. M. Beck, M. J. Gaunt, J. Am. Chem.
Soc. 2008, 130, 16184; c) T.-S. Mei, X. Wang, J.-Q. Yu, J. Am.
Chem. Soc. 2009, 131, 10806; d) B. Xiao, T.-J. Gong, J. Xu, Z.-J.
Liu, L. Liu, J. Am. Chem. Soc. 2011, 133, 1466.
[8] Reactions of organometallic reagents that are more reactive
than arylborons with electrophilic aminating reagents bearing
alkyl groups were reported. Magnesium: a) H. Tsutsui, Y.
Hayashi, K. Narasaka, Chem. Lett. 1997, 317; b) M. J. Campbell,
J. S. Johnson, Org. Lett. 2007, 9, 1521; c) T. Hatakeyama, Y.
Yoshimoto, S. K. Ghorai, M. Nakamura, Org. Lett. 2010, 12,
1516; Zinc: d) A. M. Berman, J. S. Johnson, J. Am. Chem. Soc.
2004, 126, 5680; e) A. M. Berman, J. S. Johnson, Synlett 2005,
1799; f) A. M. Berman, J. S. Johnson, J. Org. Chem. 2006, 71,
219; g) T. J. Barker, E. R. Jarvo, J. Am. Chem. Soc. 2009, 131,
15598; Titanium: T. J. Barker, E. R. Jarvo, Angew. Chem. 2011,
[19] N. Matsuda, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2011, 13,
3076.
[20] Mechanistic studies with organozinc reagents: see Ref. [8b].
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