Synthesis of N-alkoxyindol-2-ones by copper-catalyzed intramolecular N-arylation of hydroxamates

Article abstract of DOI:10.1055/s-0030-1260328

The first example of copper-catalyzed intramolecular N-arylation of hydroxamic acid derivatives is presented. Based on this transformation a new method for the synthesis of N-alkoxyindol-2-ones from 2-(2-bromoaryl) acetylhydroxamates has been developed. T

Full text of DOI:10.1055/s-0030-1260328

LETTER
2525
Synthesis of N-Alkoxyindol-2-ones by Copper-Catalyzed Intramolecular
N-Arylation of Hydroxamates
N
-Alkoxyindolo
a
nes by Cop
t
per-C
a
y
talyzed N-A
a
rylation na Kukosha, Nadezhda Trufilkina, Martins Katkevics*
Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia
Fax +37167550338; E-mail: martins@osi.lv
Received 2 June 2011
Tomkinson achieved intermolecular N-arylation of O-
substituted carbamate derivatives of hydroxylamine using
CuI14 in combination with 1,10-phenanthroline and
Cs2CO3 in DMF, or Pd(OAc)215 with a bis-pyrazole phos-
Abstract: The first example of copper-catalyzed intramolecular N-
arylation of hydroxamic acid derivatives is presented. Based on this
transformation a new method for the synthesis of N-alkoxyindol-2-
ones from 2-(2-bromoaryl)acetylhydroxamates has been developed.
The reaction conditions tolerate standard hydroxyl protecting phine ligand in toluene. However, hydroxamates were in-
effective coupling partners under these conditions.15
groups on the hydroxylamine moiety and are also applicable for the
synthesis of six-membered N-alkoxybenzolactams.
To expand the substrate scope for the transition-metal-
Key words: copper, arylation, cyclization, lactams, hydoxamic
catalyzed amidation reaction and to create a new method
acids
for the synthesis of N-oxyindolone derivatives, we decid-
ed to explore cyclization of 2-(2-bromophenyl)acetylhy-
droxamate (1a) as a model reaction (Scheme 1).
Derivatives of 1-alkoxy-1,3-dihydro-indol-2-ones are
versatile building blocks for the synthesis of indole deriv-
H
atives by reduction of the carbonyl group1 or by conver-
N
O
sion of the carbonyl group into triflate followed by cross-
coupling reaction. The N-hydroxy function in this case
O
O
N
Br
O
1a
serves as the N-protecting group that can be removed un-
der reductive conditions.1,2 In addition, N-alkoxyindol-2-
one appears as a core structure in several phytoalexins,3
gelsedine-type4 and notoamide-type5 alkaloids. N-Hy-
droxyindolin-2-one derivatives have been found to be ac-
tive against multiple sclerosis,6 as influenza endonuclease
inhibitors,7 and have also been studied as alternative cou-
pling reagents for peptide bond formation.8
2a
Scheme 1
Initially, we tested several Pd-catalyzed reaction condi-
tions that have been used for cyclization of 2-(2-bro-
mophenyl)acetamide derivatives.16–18 Pd(OAc)2 in
combination with BINAP,16 X-Phos,17 or DPEPhos18
ligand as catalyst systems did not afford product 2a, nor
did reaction conditions used for intermolecular arylation
of hydroxylamine carbamate derivatives.15 However, N-
methoxybenzolactam 2a was isolated in 29% yield, if the
reaction was carried out in the presence of 10 mol% of CuI,
20 mol% of N,N¢-dimethylethylenediamine (DMEDA)
and 2 equivalents of K2CO2 in toluene19 at 80 °C for 2
hours. Addition of molecular sieves20 to the reaction mix-
ture improved the yield of product 2a to 40%. This finding
indicated that there should be no major limitations for in-
tramolecular N-arylation of hydroxamates and was the
starting point for systematic optimization.
The title compounds can be prepared by reductive cycliza-
tion of (2-nitro-phenyl)acetic acid derivatives9 or oxida-
tion of 2,3-dihydro-1H-indoles.10 However, both methods
suffer from low functional group compatibility and vari-
ous side reactions. Alternatively, N-alkoxyindol-2-ones
may be synthesized from 2-arylacethydroxamates by
electrophilic cyclization via N-alkoxyacylnitrenium an-
ions.2,11 Although this method is widely used, the outcome
is strongly dependent on the substitution pattern of the
phenyl ring.
On the other hand, transition-metal-catalyzed cross-cou-
pling reactions are commonly applied to aryl–nitrogen
bond formation,12 although there are only three examples
in the literature where this transformation is applied to
intra- or intermolecular N-arylation of hydroxamic acid
derivatives.13–15 Yu reported cyclization of 2-arylacethy-
droxamates to N-alkyloxybenzolactams via a Pd-cata-
lyzed C–H activation reaction,13 but this method is
applicable only to a,a-disubstituted hydroxamates.
After examination of different copper sources, bases, and
solvent combinations (see Supporting Information), the
best reaction conditions [10 mol% CuBr2, 20 mol%
DMEDA, 2.0 equiv K2CO3, 3 Å MS (100% of weight),
toluene, 80 °C, 2 h] that produced N-methoxybenzolac-
tam 2a in 91% yield were identified. Application of other
ligands widely used for Cu-catalyzed cross-coupling reac-
tions, for instance proline,21 N,N¢-dimethylglycine21b or
1,10-phenanthroline,14,22 afforded lower yields of the
product 2a compared to DMEDA, while the use of salicyl-
aldoxime,20a 2,2,6,6-tetramethylheptane-3,5-dione,23 or
SYNLETT 2011, No. 17, pp 2525–2528
x
x
.x
x
.2
0
1
1
Advanced online publication: 22.09.2011
DOI: 10.1055/s-0030-1260328; Art ID: D16811ST
© Georg Thieme Verlag Stuttgart · New York

2526
T. Kukosha et al.
LETTER
2-isobutyryl-cyclohexanone23b,24 did not afford 2a at all. 93% yield from methyl 3-(2-bromo-phenyl)propionhy-
In fact, it appeared that the latter three oxygen-containing droxamate (1u) at 100 °C for 18 hours (Table 1, entry 21).
ligands might even inhibit the conversion of 1a into 2a
In conclusion, we have demonstrated the potential of cop-
since, in the absence of the ligands, the reaction proceeded
per-catalyzed intramolecular N-arylation of alkyl hydroxa-
in 9% yield.
mates. This allowed us to develop a new method for the
In order to explore the scope and limitations of the optimal synthesis of N-alkoxyindolone derivatives that can be
reaction conditions, cyclization of various hydroxamates used, with some exceptions, on a broad range of sub-
1 was performed, and the results are summarized in strates. Further investigations for N-arylation of hydroxa-
Table 1.25 N-Methoxybenzolactam was obtained in a low- mates in an intermolecular manner are in progress.
er yield from the corresponding iodo hydroxamate 1b,26
Table 1 CuBr2/DMEDA-Catalyzed Cyclization of Different
while the cyclization of chloro or trifloromethylsulfonyl
Hydroxamatesa
derivatives 1c,d did not afford the product 2a under the
same conditions.27 Standard hydroxyl protecting groups
Entry Hydroxamate
Product
Yield (%)
91
on the hydroxylamine moiety were well tolerated
(Table 1, entries 5–9); however, increased temperatures
were necessary for full conversion of bulkier benzyl,
tetrahydropyranyl, tert-butyldimethylsilyl, and tert-butyl
hydroxamates. The protection of the hydroxamic acid is
essential, otherwise the reaction proceeds in only 34%
yield (Table 1, entry 10). Interestingly, according to X-ray
crystallographic analysis,28 the product from cyclization
of hydroxamic acid 1i can be regarded as nitrone deriva-
tive 3 rather than the cyclic N-hydroxyamide in the solid
state.
H
N
O
O
1
N
O
X
O
1a X = Br
1b X = I
2a
2a
2
3
4
39
0
1c X = Cl
1d X = OTf
2a
2a
0
H
N
O
O
R1
N-Methoxybenzolactams 2k–o substituted in the phenyl
ring (Table 1, entries 11–15) were obtained in moderate to
excellent yields, although some reaction time and temper-
ature variations were necessary to achieve the optimal
outcome. Since the first step of the catalytic cycle in-
volves formation of Cu amide,19 the reaction of dibromo
derivative 1k takes place exclusively on the bromine at C-
2. The method is applicable also for the synthesis of 3,3-
dimethyl and benzylidene derivatives (2p and 2q) of indo-
lones (Table 1, entries 16, 17). However, products 2r–t
monosubstituted at 3-position were obtained in low to
moderate yields (Table 1, entries 18–20). The formation
of dimerized side products 4r–t was observed during the
course of the reaction and these were isolated in 42–46%
yield when the reactions were carried out for 18 hours
(Scheme 2). Since the yields of side products 4r–t did not
reach 50%, we assume that half of the starting hydroxam-
ate or N-methoxyindolones has been consumed as an in-
ternal oxidant29 and that the side reaction proceeds via
radical species.30
5
92
N
O
R1
O
Br
1e R1 = All
1f R1 = Bn
2e
2f
6
7
8
9
67, 84b
83b
1g R1 = THP
2g
2h
2j
1h R1 = TBDMS
1j R1 = t-Bu
81b
82b
OH
10
11
12
13
14
1i R1 = H
34
N+
O–
3
Br
H
N
Br
O
O
94
N
O
Br
O
1k
1l
2k
O
H
N
O
O
O
We have also demonstrated that the reaction conditions
are suitable for closure of six-membered rings. 1-Meth-
oxy-3,4-dihydro-1H-quinolin-2-one (5) was obtained in
92
N
O
O
Br
O
2l
H
N
O
O
68c, 76d
O
R2
O
N
CuBr2 (10 mol%)
R2
O
H
N
DMEDA (20 mol%)
O
Br
O
O
N
O
1m
2m
R2
K2CO3 (2 equiv), 3 Å MS
toluene, 80 °C, 18 h
N
O
H
Br
O
N
O
O
O
72
1r R2 = Me
N
4r 42%
4s 43%
4t 46%
F
1s R2 = 3-methylbutyl
F
Br
O
1t R2 = 3-cyclohexylmethyl
1n
2n
Scheme 2
Synlett 2011, No. 17, 2525–2528 © Thieme Stuttgart · New York

LETTER
N-Alkoxyindolones by Copper-Catalyzed N-Arylation
2527
Table 1 CuBr2/DMEDA-Catalyzed Cyclization of Different
(4) Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.;
Hydroxamatesa (continued)
Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H.
J. Nat. Prod. 2006, 69, 715.
Entry Hydroxamate
Product
Yield (%)
45e
(5) (a) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.; Hirota, H.;
Ohta, T.; Williams, R. M.; Tsukamoto, S. Angew. Chem. Int.
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2008, 71, 2064.
(6) (a) Bouerat, L.; Fensholdt, J.; Liang, X.; Havez, S.; Nielsen,
S. F.; Hansen, J. R.; Bolvig, S.; Andersson, C. J. Med. Chem.
2005, 48, 5412. (b) Bouerat, L. M. E.; Fensholdt, J.; Nielsen,
S. F.; Liang, X.; Havez, S. E.; Andersson, E. C.; Jensen, L.;
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(12) For reviews on copper-catalyzed cross-couplings, see:
(a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord.
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Sci. 2011, 2, 27.
H
O
O
N
O
O
O
15
N
O
O
Br
O
1o
2o
2p
H
N
O
82e
O
16
N
O
Br
O
1p
Ph
Ph
H
N
17
68e
O
O
O
O
N
O
Br
O
1q
2q
R2
R2
H
N
18
60
N
O
Br
O
1r R2 = Me
2r
2s
19
20
1s R2 = 3-methylbutyl
11, 32c
25
1t R2 = 3-cyclohexylmethyl 2t
O
93b,e
NH
21
N
O
O
O
Br
1u
5
a Reaction conditions: CuBr2 (10 mol%), DMEDA (20 mol%), K2CO3
(2.0 equiv), 3 Å MS (100 wt%), toluene, 80 °C, 2 h, c 0.1 mmol/mL,
(13) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(14) Jones, K. L.; Porzelle, A.; Hall, A.; Woodrow, M. D.;
Tomkinson, N. C. O. Org. Lett. 2008, 10, 797.
isolated yields.
b At 100 °C.
(15) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org.
c 5 h.
Lett. 2009, 11, 233.
d Cu2O (10 mol%) instead of CuBr2.
e 18 h.
(16) Xing, X.; Wu, J.; Luo, J.; Dai, W.-M. Synlett 2006, 2099.
(17) van den Hoogenband, A.; den Hartog, J. A. J.; Lange, J. H.
M.; Terpstra, J. W. Tetrahedron Lett. 2004, 45, 8535.
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2002, 124, 7421.
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Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J.
2004, 10, 5607. (b) Shen, Y.; Li, M.; Wang, S.; Zhan, T.;
Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 953. (c) Yao,
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the European Social Fund (No.2009/
0203/1DP/1.1.1.2.0/09/APIA/VIAA/023).
References and Notes
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Synlett 2011, No. 17, 2525–2528 © Thieme Stuttgart · New York

2528
T. Kukosha et al.
LETTER
(27) Product 2a from chloro hydroxamate 1c was obtained in
(25) General Procedure
To an oven-dried vial equipped with a stirrer bar,
hydroxamate (1.0 equiv, 0.2 mmol), copper(II) bromide (10
mol%), K2CO3 (2.0 equiv, 0.4 mmol) and 3 Å MS (100 wt%)
were added. The vial was closed using an aluminium open-
top seal with PTFE-faced septum, flushed with argon before
addition of dry toluene (2 mL) and DMEDA (20 mol%) and
stirred at the appropriate temperature for the appropriate
time (Table 1). After cooling the reaction mixture was
diluted with EtOAc (5 mL) then filtered through a short
silica plug and washed with EtOAc. The solvent was
removed in vacuo, and the crude product was purified by
flash column chromatography on silica gel eluting with
EtOAc–hexane (1:5) to give the product.
43% yield if reaction was carried out for 1 h in MeCN at
sample concentration 0.2 mmol/mL.
(28) Crystallographic data for 3 have been deposited at the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-827122, and may be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CD2 1EZ, UK; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
(29) For recent examples where the hydoxamate N–O moiety
serves as an internal oxidant, see: (a) Guimond, N.;
Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
6908. (b) Patureau, F. W.; Glorius, F. Angew. Chem. Int. Ed.
2011, 50, 1977.
(26) Compound 2a was obtained in 61% yield from iodo
hydroxamate 1b if K3PO4 was used as base. For a report of
the advantage of K3PO4 as compared to K2CO3 in copper-
catalyzed amidation of aryliodides, see ref. 19.
(30) For a review on oxidative homocoupling reactions, see:
Klussmann, M.; Sureshkumar, D. Synthesis 2011, 353.
Synlett 2011, No. 17, 2525–2528 © Thieme Stuttgart · New York

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