Copper-catalyzed direct amination of electron-deficient arenes with hydroxylamines

Article abstract of DOI:10.1021/ol200855t

The C-H amination of electron-deficient arenes such as polyfluoroarenes and azole compounds with O-acylated hydroxylamines effectively proceeds in the presence of a copper catalyst even at room temperature to provide the corresponding anilines and aminoaz

Full text of DOI:10.1021/ol200855t

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2860–2863
Copper-Catalyzed Direct Amination of
Electron-Deficient Arenes with
Hydroxylamines
Naoki Matsuda, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received April 1, 2011
ABSTRACT
The CÀH amination of electron-deficient arenes such as polyfluoroarenes and azole compounds with O-acylated hydroxylamines effectively
proceeds in the presence of a copper catalyst even at room temperature to provide the corresponding anilines and aminoazoles in good yields.
Aryl- and heteroarylamines have received much atten-
tion from synthetic chemists because of their ubiquity in
pharmaceuticals and functional materials.1 Among effi-
cient and convergent routes to the target structure is the
metal-mediated aromatic sp2CÀN bond forming reaction
(Figure 1). Since the pioneering work by Migita and
Kosugi,2 the palladium-catalyzed cross-coupling reaction
of aryl halides with amines, so-called the BuchwaldÀ
Hartwig amination,3 has been widely studied and
now provides a powerful synthetic tool for CÀN bond
formation (route a). This has largely widened the applic-
able substrates compared with the conventional Ullmann
coupling. On the other hand, recent advances in the metal-
mediated CÀH functionalization chemistry4 have enabled
the direct oxidative CÀH/NÀH coupling as a complemen-
taryand potentially more effective processfor the synthesis
of these amines (route b).5 However, most precedents are
still restricted in generality and selectivity: relatively high
temperature is required; the use ofa stoichiometric amount
of metal oxidant such as copper or silver species is inevi-
table; the reaction is often limited to an intramolecular
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) Amino
Group Chemistry, From Synthesis to the Life Sciences; Ricci, A., Eds.;
Wiley-VCH: Weinheim, 2007.
(5) With palladium, see: (a) Tsang, W. C. P.; Zheng, M.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (c) Wasa, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 14058. (d) Jordan-Hore, A. A.; Johansson,
C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 16184. (e) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 10806. (f) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am.
Chem. Soc. 2011, 133, 1466. (g) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.;
Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694. With copper, see: (h)
Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 6790. (i) Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett. 2006, 35,
842. (j) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (k) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178.
(l) Shuai, Q.; Deng, G.; Chua, Z.; Bohle, D. S.; Li, C.-J. Adv. Synth.
Catal. 2010, 352, 632. (m) Zhao, H.; Wang, M.; Su, W.; Hong, M. Adv.
Synth. Catal. 2010, 352, 1301. (n) Miyasaka, M.; Hirano, K.; Satoh, T.;
Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13, 359. With
silver, see: (o) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew.
Chem., Int. Ed. 2009, 48, 9127. With cobalt and manganese, see: (p) Kim,
J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49,
9899. Also see: (q) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed.
2010, 49, 2282.
(2) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 12, 927.
(3) Recent reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(c) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(4) Recent reviews: (a) Alberico, D. M.; Scott, E.; Lautens, M. Chem.
Rev. 2007, 107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(c) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrichchimica Acta 2007,
40, 35. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
(e) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (f)
Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (g) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (h) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (i) Kulkarni,
A. A.; Daugulis, O. Synthesis 2009, 4087. (j) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (k)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009,
48, 9792. (l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46,
677. (m) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (n)
Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096. (o)
Satoh, T.; Miura, M. Synthesis 2010, 3395. (p) Ackermann, L. Chem.
Commun. 2010, 46, 4866. (q) Hirano, K.; Miura, M. Synlett 2011, 294.
r
10.1021/ol200855t
Published on Web 05/06/2011
2011 American Chemical Society

Table 1. Optimization Studies for Copper-Catalyzed Direct
Amination of Pentafluorobenzene (1a) with O-Benzoyl-N,N-
dibenzylhydroxylamine (2a)a
3aa,
entry
Cu
ligand
phen
yield (%)b
1
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
CuI
22
14
6
2
dtbpy
Figure 1. Convergent approaches to aryl- and heteroarylamines.
3
TMEDA
PPh3
4
46
trace
46
32
5
5
PCy3
fashion. In this context, some attention is focused on the
direct amination withan electrophilic amination reagent as
the third approach (route c). Hartwig and co-workers
reported the palladium-catalyzed intramolecular direct
amination using oxime esters leading to indole deriva-
tives.6 Our group also introduced chloroamines for the
intermolecular direct amination of heteroaromatic com-
pounds and succeeded in the concise synthesis of 2-ami-
noazoles even at room temperature.7 While valuable, the
catalysis still suffered from the relatively narrow substrate
scope of the starting aromatics. For example, the applica-
tion to polyfluoroarenes8 remains unsuccessful. Therefore,
further developments of the reaction system are quite
appealing. Herein, we report the second-generation cop-
per-based catalysis for the direct amination of electron-
deficient arenes involving fluoroarenes as well as azoles.
The key to our success is the use of O-acylated hydroxyl-
amines as a modified electrophilic nitrogen source.
6
P(p-Tol)3
P(p-MeOC6H4)3
P(OPh)3
dppbz
7
8
9
9
10
11
12
13
14
15
16c
dppp
4
binap
18
11
PPh3
Cu(OTf)2
Cu(OAc)2
CuCN
PPh3
48
61
69
65 (65)
PPh3
PPh3
Cu(OAc)2
phen
a Reaction conditions: Cu (0.025 mmol), ligand (0.025 or 0.050 mmol
for bidentate or monodentate ligands, respectively), LiO-t-Bu (0.50
mmol), 1a (0.25 mmol), 2a (0.30 mmol), 1,4-dioxane (1.5 mL), rt, 4À
6 h, N2. b The yields are determined by GC method. Yield of isolated
product is in parentheses. c With 1a (0.30 mmol), 2a (0.25 mmol), and
LiO-t-Bu (0.60 mmol).
roxylamine (2a, 0.30 mmol) as model substrates (Table 1).
On the basis of our previous work,7a treatment of 1a with
2a in the presence of a Cu(acac)2/phen catalyst and LiO-t-
Bu in 1,4-dioxane afforded the corresponding directly
aminated product 3aa in 22% GC yield (entry 1). Notably,
the reaction proceeded even at room temperature albeit
with low yield. With the preliminary intriguing result in
hand, we extensively screened various combinations of
copper salts and ligands. While other nitrogen-based
ligands such as dtbpy and9 TMEDA dropped the yield
(entries 2 and 3), some monodentate phosphines improved
the reaction efficiency (entries 4À8), with PPh3 proving to
be optimal (entry 4). On the other hand, bidentate phos-
phines were detrimental (entries 9À11). Next, a variety of
copper precursors were tested using PPh3 as the ligand
(entries 12À15). Among them, CuCN and Cu(OAc)2
We began our optimization studies with pentafluoro-
benzene (1a, 0.25mmol) and O-benzoyl-N,N-dibenzylhyd-
(6) (a) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676.
Also see:(b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (c) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010,
12, 5688. (d) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc.
2010, 132, 12862.
(7) (a) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900. For CÀN bond formation with chloroamines or -
amides and organometallic reagents; see:(b) He, C.; Chen, C.; Cheng, J.;
Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew. Chem., Int. Ed. 2008, 47, 6414. (c)
Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598. (d)
Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org.
Lett. 2010, 12, 1516.
(8) Metal-catalyzed CÀH functionalization of polyfluoroarenes: ar-
ylation: (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2008, 130, 1128. (c) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc.
2010, 132, 12850. (d) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377.
Alkenylation and alkylation:(e) Nakao, Y.; Kashihara, N.; Kanyiva,
K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170. (f) Zhang, X.;
Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am.
Chem. Soc. 2010, 132, 4506. (g) Sun, Z.-M.; Zhang, J.; Manan, R. S.;
Zhao, P. J. Am. Chem. Soc. 2010, 132, 6935. Benzylation:(h) Fan, S.; He,
C.-Y.; Zhang, X. Chem. Commun. 2010, 46, 4926. Alkynylation:(i) Wei,
Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132,
2522. (j) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2010, 12, 2358. Allylation:(k) Yao, T.; Hirano, K.; Satoh,
T.; Miura, M. Angew. Chem., Int. Ed. 2011, 50, 2990. Carboxylation:(l)
Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132, 8858.
Stannylation:(m) Doster, M. E.; Hatnean, J. A.; Jeftic, T.; Modi, S.;
Johnson, S. A. J. Am. Chem. Soc. 2010, 132, 11923 and ref 5k, 5m.
(9) The NÀO bond as a useful handle for CÀN bond formation; see:
(a) Erdick, E.; Ay, M. Synth. React. Inorg. Met.-Org. Chem. 1989, 19,
663. (b) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 26,
€
317. (c) Noack, M.; Gottlich, R. Chem. Commun. 2002, 536. (d) Berman,
A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680. (e) Berman,
A. M.; Johnson, J. S. Synlett 2005, 1799. (f) Berman, A. M.; Johnson,
J. S. J. Org. Chem. 2006, 71, 219. (g) Campbell, M. J.; Johnson, J. S. Org.
Lett. 2007, 9, 1521. (h) Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org. Lett.
2008, 10, 3005. (i) Hirano, K.; Satoh, T.; Miura, M. Org. Lett. ASAP,
10.1021/ol100651r. Alkali-metal-mediated amination of thiadiazoles
with NH2ÀOH: (j) Rao, V. R.; Srinivasan, V. R. Indian J. Chem.
1965, 3, 417.
Org. Lett., Vol. 13, No. 11, 2011
2861

showed good performances (entries 14 and 15). Some
additional investigations into the reaction stoichiometry
revealed that the use of 2a as the limiting reagent under a
Cu(OAc)2/phen system gave better generality and repro-
ducibility, and the desired 3aa was isolated in 65% yield
(entry 16). Any changes of reaction solvent and base into
toluene, DMSO, K3PO4, and NaO-t-Bu diminished the
yield of 3aa (not shown).10
Table 2. Copper-Catalyzed Direct Amination of Fluoroarenes 1
with Various O-Benzoylhydroxylamines (2)a
By using the Cu(OAc)2/phen catalyst, the direct amina-
tion of an array of fluoroarenes 1 with 2a was carried out
(Scheme 1). In addition to 1a, 3-substituted 1,2,4,5-tetra-
fluorobenzene derivatives bearing not only electron-with-
drawing but also electron-donating groups underwent
CÀH amination, although the latter showed somewhat
lower reactivity (3baÀea). The pyridine skeleton was also
available for use (3fa). On the other hand, 1,2,4,5-tetra-
fluorobenzene and 1,2,3,5-tetrafluorobenzene that contain
two possible reactive CÀH bonds provided the monoami-
nated products exclusively albeit with moderate efficiency
(3ga and 3ha). However, the reaction of 1,3,5-trifluoro-
benzene was sluggish (3ia), indicating that the step of CÀH
bond cleavage highly depends on its acidity.11
Scheme 1. Copper-Catalyzed Direct Amination of Various
Fluoroarenes 1 with O-Benzoyl-N,N-dibenzylhydroxylamine
(2a)a
a Reaction conditions: see Table 1, entry 16. b Yield of isolated
product.
N-benzyl-N-methyl, and N,N-diallyl substituent patterns
were tolerated toward the reaction (entries 1À6). In parti-
cular, the resultant benzyl12 and allyl13 moieties could
be readily deprotected into the free NÀH bond, which
are versatile handles for further transformations. Cyc-
lic systems such as pyrrolidine, piperidine, and mor-
pholine also participated in the coupling without any
difficulties (entries 7À9). Moreover, the Boc-protected
piperazine and bicyclic framework, tetrahydroisoquino-
line, could be introduced to the polyfluorinated arene
directly (entries 10 and 11). It is noteworthy that the
secondary amino group was compatible under the reaction
conditions (entry 12).
a Reaction conditions: see Table 1, entry 16. bAt 80 °C.
A plausible mechanism for the copper-catalyzed direct
amination of pentafluorobenzene (1a) with O-benzoyl-N,
N-dibenzylhydroxylamine (2a) is illustrated in Scheme 2.
We subsequently investigated the scope of amines 2
(Table 2). Several acyclic substrates containing N,N-diethyl,
(12) Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2007, 72, 2040.
(13) (a) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman,
D. G. Tetrahedron Lett. 1998, 39, 1313. (b) Cadierno, V.; Garcıa-
Garrido, S. E.; Gimeno, J.; Nebra, N. Chem. Commun. 2005, 4086.
(10) Without any copper catalysts, no formation of 3aa was detected
by gas chromatography analysis.
(11) For pKa values of representative fluoroarenes; see: Shen, K.; Fu,
Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63, 1568.
2862
Org. Lett., Vol. 13, No. 11, 2011

effect of an OAc ancillary ligand and the detailed mechan-
ism for CÀN bond formation still remain obscure, and
further efforts are required for uncovering the process.17
Finally, we applied the above copper catalysis to rela-
tively acidic azoles (Scheme 4). Pleasingly, the direct
amination of 1,3,4-oxadiazoles, benzoxazole, and ben-
zothiazole took place under standard conditions to furnish
the corresponding 2-aminoazoles 8abÀcb, 9ab, and 10ab in
moderate to good yields. The wider substrate scope is
suggestive of superiority of the present catalysis based on
hydroxylamines as the electrophilic amination reagents,
compared to the previous system using chloroamines.7a
Scheme 2
Scheme 4
Scheme 3
In conclusion, we have developed a copper-catalyzed
direct amination of electron-deficient arenes involving
fluoroarenes and azoles with O-acylated hydroxylamines.
The catalysis enabled the rapid and concise construction of
polyfluoroanilines18 and aminoazoles,19 which are of im-
portance in pharmaceutical and medicinal chemistry.
Initial reduction of Cu(II) into Cu(I)14 and complexation
with phen and LiO-t-Bu forms the copper alkoxide 4.
Subsequent direct cupration of 1a with the aid of an
anionic O-t-Bu ligand of strongly basic nature15 generates
the arylcopper species 5 as the key intermediate. The CÀN
bond-forming reaction then occurs to provide the ami-
nated product 3aa along with the CuOBz complex 6. Final
ligand exchange with LiO-t-Bu regenerates the starting
active catalyst 4 to complete the catalytic cycle. The results
ofthe reactionswiththe isolated(phen)CuC6F5 (7)16 under
both stoichiometric and catalytic conditions are consistent
with the proposed pathway (Scheme 3). However, the
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) For mechanistic studies with organozinc reagents, see: ref 9g.
At this stage, a radical pathway could not be completely excluded; see:
ref 9c.
(14) The detailed mechanism for the reduction is not clear at this
stage.
(15) For O-t-Bu ligand-assisted direct cupration, see: (a) Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (b) Yotphan, S.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11, 1511. (c) Besselievre,
(18) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(19) (a) Yale, H. L.; Losee, K. J. Med. Chem. 1966, 9, 478. (b) Omar,
F.; Mahfouz, A. N. M.; Rahman, M. A. Eur. J. Med. Chem. 1996, 31,
819. (c) Sato, Y.; Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.;
Nizato, T.; Suzuki, K.; Konno, F. J. Med. Chem. 1998, 41, 3015. (d)
Laddi, U. V.; Desai, S. R.; Bennur, R. S.; Bennur, S. C. Indian J.
Heterocycl. Chem. 2002, 11, 319. (e) Rostom, S. A. F.; Shalaby, M. A.;
El-Demellawy, M. A. Eur. J. Med. Chem. 2003, 38, 959. (f) Yoshida, S.;
Watanabe, T.; Sato, Y. Bioorg. Med. Chem. 2007, 15, 3515.
ꢀ
F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553. (d) Zhang, L.;
Cheng, J.; Ohnishi, T.; Hou, Z. Angew. Chem., Int. Ed. 2010, 49, 8670. (e)
Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2010, 75, 1764 and refs 7a and 8iÀ8k.
(16) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185.
Org. Lett., Vol. 13, No. 11, 2011
2863