Iron-catalyzed aryl-aryl cross-coupling reaction tolerating amides and unprotected quinolinones

Article abstract of DOI:10.1039/b618617c

The iron(III)-catalyzed cross-coupling reaction between functionalized arylcopper reagents and aromatic iodides bearing an amide function or an unprotected quinolinone leads smoothly to polyfunctionalized biphenyls in excellent yields due to an intramolec

Full text of DOI:10.1039/b618617c

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Iron-catalyzed aryl–aryl cross-coupling reaction tolerating amides and
unprotected quinolinones{
Christiane C. Kofink, Benoˆıt Blank, Sandro Pagano, Nadine Go¨tz and Paul Knochel*
Received (in Cambridge, UK) 20th December 2006, Accepted 26th January 2007
First published as an Advance Article on the web 16th February 2007
DOI: 10.1039/b618617c
The iron(III)-catalyzed cross-coupling reaction between
functionalized arylcopper reagents and aromatic iodides bear-
ing an amide function or an unprotected quinolinone leads
smoothly to polyfunctionalized biphenyls in excellent yields due
to an intramolecular chelating effect of the amide group.
Transition-metal catalyzed cross-coupling reactions are powerful
tools for the formation of new carbon–carbon bonds between
C(sp2)-centers.1 Most catalytic systems used are based on
Scheme 2 Preparation of highly functionalized quinolinones of type 5.
palladium or nickel.2,3 These metals are costly or toxic and often
require expensive and sophisticated ligands.4 There is a great need
Table 1 Iron-catalyzed cross-coupling of unprotected quinolinones
of type 4 using arylcopper reagents of type 1 leading to highly
functionalized quinolinones of type 5
for cheap and environmentally friendly catalysts which do not
require complicated ligands. Based on the pioneering work of
Kochi,5 several reports were published using iron salts as catalysts
to perform a cross-coupling reaction between a Grignard reagent
and an alkyl or alkenyl halide.6,7 Recently, we have reported
an iron-catalyzed aryl–aryl cross-coupling reaction using
polyfunctionalized copper reagents for the preparation of highly
functionalized biphenyls.8
Entry
1
ArCua
Electrophile
Product
Yieldb (%)
91
Herein, we wish to report an iron-catalyzed cross-coupling
reaction of arylcopper reagents with aryl iodides bearing amide
functions or with unprotected iodo-quinolinones. Copper organo-
metallics of type 1 are prepared via an iodine–magnesium exchange
or a direct Mg-insertion, followed by transmetalation with
CuCN?2LiCl. These copper derivatives are treated with a
2-iodophenyl amide or quinolinones of type 2 and Fe(acac)3
(10 mol%). The reaction takes place in THF–DME (3 : 2) at 80 uC
and leads to highly functionalized biphenyls of type 3 (Scheme 1).
To delineate the synthetic scope of our method, we have
synthesized several heterocyclic compounds and found that
2
3
4
5
84
74
96
88
Scheme 1 Iron-catalyzed cross-coupling between arylcopper reagents of
type
1 and 2-iodoamides or quinolinones of type 2 leading to
functionalized biphenyls of type 3.
Ludwig-Maximilians-Universita¨t, Department Chemie und Biochemie,
Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstr. 5-13, Haus F,
81377, Mu¨nchen, Germany. E-mail: paul.knochel@cup.uni-
muenchen.de; Fax: +49 (0) 89 2180 77680; Tel: + 49 (0) 89 2180 77679
{ Electronic supplementary information (ESI) available: Experimental
procedures and full characterization of all new compounds. See DOI:
10.1039/b618617c
a
b
ArCu(CN)MgBr or ArCu(CN)MgCl.
analytically pure product.
Isolated yield of
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functionalized quinolinones9 of type 4 are excellent electrophiles.
This method proved to be very efficient for the preparation of
highly functionalized quinolinone derivatives of type 5 (Scheme 2
and Table 1).
Table 3 Preparation of highly functionalized biphenyls of type 7
Entry ArCua
Electrophile
Productb
Yieldc (%)
1
75
Both, arylcuprates with electron-rich substituents, such as a
methoxy group, as well as arylcuprates bearing electron-
withdrawing substituents, undergo this iron-catalyzed cross-
coupling reaction in excellent yields. The reaction of the
electron-rich 4-methoxyphenylcopper 1a with quinolinone deriva-
tives 4a and 4b leads to the desired products 5a and 5b in 91 and
84% yield, respectively (entries 1 and 2, Table 1). Furthermore,
Grignard reagents bearing electron-withdrawing groups such as
nitrile 1b or an ester 1c can be used, to perform this cross-coupling
reaction with different quinolinone derivatives 4a and 4b. The
functionalized quinolinones 5c–5e can be obtained in yields up to
96% (74–96%, entries 3–5, Table 1).
2
3
4
70
82
84
We then examined the use of secondary amides as electrophiles
under these reaction conditions. Therefore, we screened several
benzamides of type 2 in the reaction with 4-methoxyphenylcopper
1a in order to investigate the influence of various amides on the
formation of products of type 3 (Scheme 3, Table 2).
We observed that the nature of the acyl group has a strong
influence on the reactivity (Table 2).
5
96
We found that electron-donating substituents led to the highest
isolated yield of the products of type 3. Also, by comparing a tosyl
or triflyl protecting group, we observed that the more electron-
donating tosylate leads to higher yields (68–84%, entries 5 and 6,
Table 2). Other protecting groups such as an acetyl, trifluoroacetyl
or benzoyl group gave less satisfactory yields (55–85%, entries 1–3,
Table 2).
6
7
70
71
The 4-methoxybenzoyl group gave the best protection, with the
strongest intramolecular chelating effect, and led to the highest
isolated yields (92%, entry 4, Table 2). Therefore, functionalized
benzanilides of type 6 were used for further cross-coupling
reactions leading to highly functionalized biphenyls of type 7, as
shown in Table 3.
The iron-catalyzed cross-coupling of various functionalized
amides showed surprising results. Amides with electron-donating
8
74
9
92
78
Scheme 3 Fe(III)-catalyzed cross-coupling with benzanilides.
10
Table 2 Screening of different protecting groups R on derivatives of
type 2
Entry
Protecting group R
Derivative 3 yielda (%)
1
2
3
4
5
6
a
2a: CF3CO
2b: MeCO
2c: PhCO
2d: p-MeOC6H4CO
2e: CF3SO2
2f: TolSO2
3a: 55
3b: 74
3c: 85
3d: 92
3e: 68
3f: 84
a
b
ArCu(CN)MgBr or ArCu(CN)MgCl.
Isolated yield of analytically pure product.
R
=
CO(C6H4OMe).
c
substituents yielded the products in 10–20% higher yields than with
electron-withdrawing substituents, which is unusual. This may be
best explained by assuming that donor-substituents influence the
Isolated yield of analytically pure product.
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chelating effect of the amide function. The reaction of the
protected aldehyde 1d with the ester- and nitrile-substituted amides
gave compounds 7a and 7b in 70–75% yield. The TIPS-protected
phenol 6c led to the sterically hindered compound 7c in 82% yield
(entries 1–3, Table 3). Using 4-cyanophenylcopper 1e and amides
6d and 6c the desired products 7d and 7e could be prepared in
excellent yields (84–96%, entries 4 and 5, Table 3). The reaction of
3-cyanophenylcopper 1f gave the derivative 7f in 70% yield (entry 6,
Table 3). Furthermore, electron-rich arylcopper species such as
compounds 1g or 1h could be reacted with various amides 6b and
6d leading to the products 7g and 7h in good yields (71–74%,
entries 7 and 8, Table 3). Using an ortho-carbethoxyphenylcopper
1i as nucleophile, an intramolecular cyclization with the amide
took place and led in situ to the phenanthridinone derivatives 7i
and 7j in 92 and 78% yields, respectively (entries 9 and 10, Table 3).
In summary, we have found a very efficient iron-catalyzed cross-
coupling reaction for the preparation of polyfunctionalized
biphenyls bearing secondary amide functions. Furthermore, this
iron-catalyzed protocol provides an straightforward synthesis of
functionalized phenanthridinones, which are intensively studied as
potential therapeutic agents, due to their properties as poly(ADP-
ribose)polymerase-1 (PARP-1) inhibitors.10 In addition, this
method offers an easy access to highly functionalized unprotected
quinolinone derivatives. Further extensions of this iron-catalyzed
reaction are underway in our laboratories.
C. K. thanks the DFG for a fellowship. We thank the Fonds der
Chemischen Industrie, Chemetall GmbH (Frankfurt), Degussa
AG (Frankfurt), BASF AG (Ludwigshafen) for the generous gift
of chemicals.
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1956 | Chem. Commun., 2007, 1954–1956
This journal is ß The Royal Society of Chemistry 2007