Copper-catalyzed annulative amination of ortho -alkynylphenols with hydroxylamines: Synthesis of 3-aminobenzofurans by umpolung amination strategy

Article abstract of DOI:10.1021/ol200651r

Chemical equations presented. A room temperature copper-catalyzed annulative amination of ortho-alkynylphenols with electrophilic amination reagents, O-acylated hydroxylamines, proceeds efficiently to provide the corresponding 3-aminobenzofurans of biolog

Full text of DOI:10.1021/ol200651r

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2395–2397
Copper-Catalyzed Annulative Amination of
ortho-Alkynylphenols with Hydroxylamines:
Synthesis of 3-Aminobenzofurans by
Umpolung Amination Strategy
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 March 11, 2011
ABSTRACT
A room temperature copper-catalyzed annulative amination of ortho-alkynylphenols with electrophilic amination reagents, O-acylated
hydroxylamines, proceeds efficiently to provide the corresponding 3-aminobenzofurans of biological and pharmaceutical interest.
Aminobenzofuran and its derivatives may constitute an
important class of heteroarylamines, which are of current
interest in biological and pharmaceutical sciences.1 Recent
advances in the palladium-catalyzed cross-coupling reac-
tion of aryl halides and amines, that is the Buchwaldꢀ
Hartwig amination,2 provide a powerful synthetic tool for
the construction of this type of compound.
aromatic CꢀH bonds and succeeded in the copper-catalyzed
rapid and concise synthesis of the corresponding heteroaryl-
amines even at room temperature.3,4 In this context, we may
envisage that the electrophilic, umpolung amination strategy
could be applicable to the efficient synthesis of 3-aminobenzo-
furan derivatives. Thus, our blueprint consists of (i) initial
annulative cupration of ortho-alkynylphenols5 and (ii) an
electrophilic CꢀN bond forming reaction (Scheme 1). If the
process were feasible, it would enable an orthogonal and
complementary access to aminobenzofuran structures. In-
deed, we have found that the process can be realized by
employing O-acylated hydroxylamines as the amination
reagents, while chloroamines are ineffective.
Meanwhile, we have recently introduced chloroamines
as new, effective electrophilic amination reagents for hetero-
(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.
(2) Reviews: (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.
(3) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc.
2010, 132, 6900.
(4) NꢀCl or NꢀO bond as a useful handle for CꢀN bond formation:
(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) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680.
(d) Berman, A. M.; Johnson, J. S. Synlett 2005, 1799. (e) Berman, A. M.;
Johnson, J. S. J. Org. Chem. 2006, 71, 219. (f) Campbell, M. J.; Johnson,
J. S. Org. Lett. 2007, 9, 1521. (g) Zhang, Z.; Yu, Y.; Liebeskind, L. S.
Org. Lett. 2008, 10, 3005. (h) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu,
W.; Li, Q.; Lei, A. Angew. Chem., Int. Ed. 2008, 47, 6414. (i) Barker, T. J.;
Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598. (j) Tan, Y.; Hartwig,
J. F. J. Am. Chem. Soc. 2010, 132, 3676. (k) Guimond, N.; Gouliaras, C.;
Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (l) Too, P. C.; Wang,
Y.-F.; Chiba, S. Org. Lett. 2010, 12, 5688. (m) Hatakeyama, T.;
Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org. Lett. 2010, 12, 1516.
Scheme 1
r
10.1021/ol200651r
2011 American Chemical Society
Published on Web 03/30/2011

Table 1. Optimization Studies for Annulative Coupling of
2-(Phenylethynyl)phenol (1a) with O-Benzoyl-N,N-diethylhy-
droxylamine (2a)a
Scheme 2. Copper-Catalyzed Annulative Coupling of ortho-Alky-
nylphenols 1 with O-Benzoyl-N,N-diethylhydroxylamine (2a)
3aa,
entry
Cu/ligand
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/dtbpy
Cu(acac)2/phen
Cu(acac)2/bpy
Cu(acac)2/2PPh3
Cu(acac)2/dppe
Cu(acac)2
CuCl2
CuCN
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
none
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
NaO-t-Bu
KO-t-Bu
Cs2CO3
DMSO
DMF
NMP
toluene
THF
14
18
39
0
0
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
20
38
20
0
47
9
11
63
92 (61)c
11
trace
0
9
10
11
12
13
14
15
16
17
18
LiO-t-Bu
0
a A mixture of Cu salt (0.050 mmol), base (1.0 mmol), 1a (0.50 mmol),
and 2a (0.60 mmol) in solvent (3.0 mL) was stirred at room temperature for
4 h under N2. b Yield determined by GC. Yield of isolated product in
parentheses. c The lower isolated yield is due to the partial decomposition of
3aa during chromatographic purification, while the compound is stable after
isolation. See Supporting Information for details.
a With 1.0 mmol of 2a.
was obtained with Cu(OTf)2 (entries 10ꢀ14). Alternative
bases including NaO-t-Bu, KO-t-Bu, and Cs2CO3 were detri-
mental (entries 15ꢀ17). Without any copper catalyst, the
reaction did not occur (entry 18). Thus, the reaction pro-
ceeded very smoothly in the presence of Cu(OTf)2 and LiO-t-
Bu in NMP even at room temperature and completed within
4 h (entry 14), the conditions being remarkably milder than
those for the precedent similar types of reaction of 1a.5
With the optimized conditions in hand, the oxyamina-
tion of a variety of ortho-alkynylphenols 1 was carried out
(Scheme 2). The substrate with an electron-donating methoxy
group showed comparable reactivity (3ba), while electron-
withdrawing trifluoromethyl and chloro substituents resulted
in a somewhat lower efficiency (3caꢀda). In addition to the
benzene ring, the heteroaryl function, thiophene was tolerant
toward the reaction (3ea). Moreover, the conjugated enyne
system 1f (R1 = H, R2 = 1-cyclohexenyl) could be converted
to 3fa with the olefin moiety left intact. It is noteworthy that
the copper catalysis accommodated alkyl substitutions at the
alkyne terminus: primary, secondary, and tertiary alkyl-sub-
stituted ortho-alkynylphenols reacted with 2a without any
difficulties (3gaꢀia). The 4,6-disubstituted pattern on phenol
was also available for use (3jaꢀka), and especially, 3ja could
enjoy further manipulation of the remaining CꢀCl functions.
We then performed the reaction of 1g with an array of
O-benzoylhydroxylamines 2 (Table 2). Acyclic allyl- and
benzylamines 2b and 2c formed the corresponding
We initially selected 2-(phenylethynyl)phenol (1a) and
O-benzoyl-N,N-diethylhydroxylamine (2a) as model sub-
strates. In an early examination, treatment of 1a with 2a in
thepresenceofCu(acac)2/dtbpy (dtbpy = 4,40-di(tert-butyl)-
2,20-bipyridine) and LiO-t-Bu as catalyst and base, respec-
tively, in DMSO provided 3-(N,N-diethylamino)benzofuran
(3aa) in 14% yield (GC) (Table 1, entry 1).6 The choice of
solvent was critical: aprotic polar solvents were effective, with
NMP proving to be optimal, while the formation of 3aa was
not detected in less polar toluene or THF (entries 1ꢀ5). Al-
though other nitrogen- and phosphorus-based ligands were
investigated, Cu(acac)2 itself afforded a better yield (entries
6ꢀ10). Among the various copper salts tested, the best result
(5) Metal-mediated sequential CꢀO/CꢀC bond-forming reactions with
ortho-alkynylphenols: (a) Arcadi, A.; Cacchi, S.; Rosario, M. D.; Fabrizi,
G.; Marinelli, F. J. Org. Chem. 2004, 69, 2235. (b) Hu, Y.; Nawoschilk, K. J.;
Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem. 2004, 69, 2235. (c)
Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew. Chem., Int. Ed.
2006, 45, 944. (d) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org.
Lett. 2006, 8, 2803. (e) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed.
2007, 46, 2074. (f) Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura, E.
ꢀ
J. Am. Chem. Soc. 2007, 129, 11902. (g) Martınez, C.; Alverez, R.;
Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083. (h) Isono, N.; Lautens, M.
Org. Lett. 2009, 11, 1329. (i) Swamy, N. K.; Yazici, A.; Pyne, S. G. J. Org.
ꢀ
Chem. 2010, 75, 3412. (j) Alverez, R.; Martınez, C.; Madich, Y.; Denis, J. G.;
ꢀ
Aurrecoechea, J. M.; de Lera, A. R. Chem.;Eur. J. 2010, 16, 12746.
(6) The detectable byproduct was simply cyclized product, 2-phenyl-
benzofuran.
2396
Org. Lett., Vol. 13, No. 9, 2011

Table 2. Copper-Catalyzed Annulative Coupling of ortho-
Alkynylphenol 1g with O-Benzoylhydroxylamines 2a
Scheme 3
corresponding 3-aminobenzofuran 3lg was produced, leav-
ing the two terminal olefin moieties untouched. Subsequent
ruthenium-catalyzed cycloisomerization9 afforded the de-
sired tricyclic framework 4 in 77% yield.
Although the exact mechanism remains unclear at this
stage, some observations are to be noted: the control
experiment of 2-(4-methoxyphenyl)benzofuran with 2a un-
der identical conditions resulted in no formation of 3ba (vs
Scheme 2); Cu(OTf)2 of a more π-acidic nature worked
much better than CuCl2, Cu(acac)2, and CuCN (Table 1);
Lewis basic ligands (to the copper center) such as diamines
and phosphines gave negative effects on yield (Table 1).
These phenomena support that the reaction would be
triggered by the nucleophilic oxymetalation of alkyne acti-
vated through the π-coordination to Cu(II),10 which is
consistent with our initial working hypothesis. Further
efforts on elucidation of the detailed mechanism involving
the CꢀN bond-forming step11 are ongoing.12
a A mixture of Cu(OTf)2 (0.050 mmol), LiO-t-Bu (1.0 mmol),
1g (0.50 mmol), and 2 (1.0 mmol) in NMP (3.0 mL) was stirred at room
temperature for 4 h under N2. b Yield of isolated product.
3-aminobenzofurans 3gb and 3gc, respectively, the additional
derivatization of which could be easily operative after the
appropriate deprotection (entries 1 and 2).7 Cyclic systems
were also compatible toward the reaction (entries 3ꢀ5).
Thus, piperidine-, morpholine-, and tetrahydroisoquino-
line-substituted benzofurans 3gdꢀgf were obtained with
substantial yields.
To demonstrate the synthetic utility of the present pro-
cess, a two-step synthesis of the benzofuro[3,2-b]azepine
core, which is found in potent inhibitors of bone resorption,8
was carried out (Scheme 3). When ortho-(3-methyl-3-buten-
1-yn-1-yl)phenol (1l) was subjected to our oxyamination
with N-allyl-O-benzoyl-N-methylhydroxylamine (2g), the
In conclusion, we have developed an effective copper-
catalyzed annulative amination of ortho-alkynylphenols
with O-acylated hydroxylamines. The reaction system may
compensate for the precedents13 and provide a new, facile
route to the 3-aminobenzofuran skeletons of biological
and pharmaceutical interest. Further efforts seek to apply
the methodology to alkene analogues and the synthesis of
other heteroarylamines.
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan.
(7) Selected examples: (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. (c) Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2007, 72, 2040.
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.
(8) (a) Kawai, Y.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K.; Yatabe,
T.; Oku, T. PCT Int. Appl. 1995, WO 9529907, A1 19951109 (CAN
124:202000). Also see: (b) Cho, H.; Wakitani, Y. Jpn. Kokai Tokkyo Koho
1997, JP 09020779, A 19970121 (CAN 126:186116). (c) Cho, H.; Wakitani, Y.
PCT Int. Appl. 1997, WO 9717349, A1 19970515 (CAN 127:5023). (d) Kondo,
K.; Yamashita, H.; Kitano, K.; Shinohara, Y.; Kan, K.; Ogawa, H.; Mori, T. Jpn.
Kokai Tokkyo Koho 1999, JP 11001456, A 19990106 (CAN 130:139333).
(9) Cycloisomerization of N-allyl-2-vinylanilines catalyzed by ruthe-
nium hydrides generated in situ from Grubbs’ catalysts and vinyl ethers:
(a) Terada, Y.; Arisawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004,
43, 4063. (b) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J. Org. Chem. 2006, 71, 4255. However, this isomerization
mode was unprecedented, to the best of our knowledge. This unique
reactivity is probably due to the benzofuran system and methyl sub-
stitution at the olefinic moiety.
(10) (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395.
(b) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126.
(11) Mechanistic studies with organozinc reagents: ref 4f.
(12) At this stage, an alternative pathway involving a radical species
€
could not be completely excluded; see: Noack, M.; Gottlich, R. Chem.
Commun. 2002, 536.
(13) Alternative accesses: (a) Sakai, N.; Uchida, N.; Konakahara, T.
Tetrahedron Lett. 2008, 49, 3437. (b) Li, H.; Liu, J.; Li, Y. Tetrahedron
Lett. 2009, 50, 2353. (c) Ramazani, A.; Mahyari, A. T.; Rouhani, M.;
Rezaei, A. Tetrahedron Lett. 2009, 50, 5625.
Org. Lett., Vol. 13, No. 9, 2011
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