Lewis acid-triggered selective zincation of chromones, quinolones, and thiochromones: Application to the preparation of natural flavones and isoflavones

Article abstract of DOI:10.1021/ja306178q

A Lewis acid-triggered zincation allows the regioselective metalation of various chromones and quinolones. In the absence of MgCl₂, a C(3) zincation is observed, whereas in the presence of MgCl₂ or a related Lewis acid, C(2) zincation occurs. Applications to a natural flavone, isoflavone, and quinolone are shown.

Full text of DOI:10.1021/ja306178q

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Communication
“Lewis acid Triggered Selective Zincation of Chromones,
Quinolones and Thiochromones. Application to the
Preparation of Natural Flavones and Isoflavones”
Lydia Magdalena Klier, Tomke Bresser, Tobias Alexander Nigst, Konstantin Karaghiosoff, and Paul Knochel
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja306178q • Publication Date (Web): 03 Aug 2012
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Lewis acid Triggered Selective Zincation of Chromones,
Quinolones and Thiochromones. Application to the Prepara-
tion of Natural Flavones and Isoflavones**
9
Lydia Klier, Tomke Bresser, Tobias A. Nigst, Konstantin Karaghiosoff, and Paul Knochel*,†
†Department Chemie, LudwigꢀMaximiliansꢀUniversitaet Muenchen, Butenandtstr. 5ꢀ13, Haus F, 81377 Munich,
paul.knochel@cup.uniꢀmuenchen.de
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KEYWORDS: chromone ꢁ Lewis acid ꢁ metalation ꢁ TMPꢀbase ꢁ zinc
Scheme 1. MgCl2-triggered regioselective zincation of chromone
(6) and N-methyl-4- quinolone (7).
ABSTRACT: A Lewis acid triggered zincation allows the
regioselective metalation of various chromones and quinꢀ
olones. In the absence of MgCl2, a C(3)ꢀzincation is observed,
whereas in the presence of MgCl2 or a related Lewis acid
C(2)ꢀzincation occurs. Application to a natural flavone, isoflaꢀ
vone and quinolone is shown.
Chromones and quinolones are important classes of natural
products,1 which have useful pharmaceutical properties, such as
antineoplastic, antibacterial and antiꢀHIV activity.2 Typical repreꢀ
sentative natural products are chrysin (1),3 the isoflavone bioꢀ
chanin A (2)4 and the quinolone graveolinine (3).5 Thiochroꢀ
mones, which are not found as natural products, also show useful
bioactivities.6,7 Consequently, the functionalization of these hetꢀ
erocyclic scaffolds is of special synthetic importance.
The lithiation at position C(3) and position C(2) of the chroꢀ
mone scaffold and further functionalizations have only been briefꢀ
ly described. A good metalation selectivity between position C(2)
and C(3) has yet not been achieved.8,9 The lithiation of unsubstiꢀ
After metalation, the zinc reagents 9 and 10 would be obtained.
We expected that in the presence of a strong Lewis acid such as
MgCl2, complexation at the carbonyl group would occur. In this
case, the coordination of the TMPꢀzinc moiety would proceed at
heteroatom Y(1) forming complex 11 and resulting in the C(2)ꢀ
zincated heterocycles 12 or 13 after deprotonation (pathway b,
Scheme 1). Herein, we wish to report the successful realization of
these regioselective zincations of chromone (6) and Nꢀmethylꢀ4ꢀ
quinolone (7) according to Scheme 1. Thus, we have treated
chromone (6) with TMPZnClꢁLiCl (4), which resulted in a selecꢀ
tive zincation at position C(3) to produce the zinc reagent 9. After
iodolysis, 3ꢀiodoꢀchromone (14a) was isolated (entry 1, Table 1).
Transmetalation of 9 with CuCNꢁ2LiCl,23 and subsequent reaction
with allylic bromides provided the chromones 14b-c (entries 2ꢀ3).
The reaction with pivaloyl chloride afforded the expected ketone
14d (entry 4). Pdꢀcatalyzed Negishi crossꢀcoupling24 with aryl
iodides or aryl bromides led to the crossꢀcoupling products 14e-i
(entries 5ꢀ9).
tuted
chromone
with
TMPꢀLi
(TMP =
2,2,6,6ꢀtetramethylpiperidyl) or LDA (lithium diisopropylamide)
produces a complex mixture of products,8,9 and therefore, the use
of more selective metalating agents is desirable. Also, a selective
zirconation10 of chromone and a Pdꢀcatalyzed direct intermolecuꢀ
lar alkenylation11 at position C(3) have been disclosed. A selecꢀ
tive C(2) lithiation of quinolone with LDA has also been deꢀ
scribed.12
Recently, we have reported the preparation of new highly
chemoselective TMPꢀbases such as TMPZnClꢁLiCl (4)13 and
TMP2Znꢁ2MgCl2ꢁ2LiCl (5).14 These hindered zinc amides display
an exceptional kinetic15 basicity and tolerate a broad range of
functional groups. We have also shown that various Lewis acids
are compatible with such Mgꢀ and ZnꢀTMPꢀbases and constitute a
new class of frustrated Lewis pairs.16 Thus, the metalation regiꢀ
oselectivity of pyridines with TMPꢀbases was triggered by the
presence of BF3ꢁOEt2.17 Also, magnesium salts,18 triorganoboꢀ
ranes19 and catalytic amounts of Sc(OTf)3 20 influence the reactiviꢀ
ty of organometallics. Based on these recent advances, we have
envisioned that the presence (or absence) of Lewis acids may
direct the zincation of chromone (6) or Nꢀmethylꢀquinolone (7)
either in position C(2) or C(3). Theoretical calculations showed
that the thermodynamically most acidic hydrogen is attached to
C(2).21 However, the most basic oxygen is located at the carbonyl
group of these heterocycles. We anticipated that TMPZnClꢁLiCl
(4) would coordinate at this oxygen leading through the complexꢀ
induced proximity effect (CIPE)22 to complexes of type 8 (pathꢀ
way a, Scheme 1).
Table 1. Products obtained by the zincation of chromone (6) with
TMPZnClꢁLiCl (4) and subsequent reaction with electrophiles.
entry
1
electrophile
I2
product
yielda
77%
14a
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Negishi crossꢀcoupling furnished the expected C(2)ꢀsubstituted
chromones 15b-e.
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8
2
3
4
5
14b
14c
14d
14e
87%b
75%b
74%b
90%
2,3ꢀDisubstituted chromones can be readily prepared by two
successive metalation / crossꢀcoupling sequences (Scheme 3).
Pdꢀcatalyzed crossꢀcoupling of C(2)ꢀzincated chromone 12 with
p-iodobenzotrifluoride afforded first the C(2)ꢀsubstituted flavone
16 (Scheme 3) and then the 2,3ꢀdisubstituted chromone 17 after
treatment with TMPZnClꢁLiCl (4) and subsequent Negishi crossꢀ
coupling reaction.
Scheme 3. Reagents and conditions for the preparation of the bis-
functionalized chromone 17.
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tBuCOCl
(a) 1) TMP2Znꢁ2MgCl2ꢁ2LiCl (5, 0.6 equiv, ꢀ30 °c; 1 h), THF, ꢀ30 °C,
1 h; 2) 2% Pd(dba)2, 4% tfp, ArI, 25 °C, 1 h; (b) 1) TMPZnClꢁLiCl
(4, 1.2 equiv, 25 °C, 0.5 h), THF, 25 °C, 30 min; 2) 2% Pd(dba)2, 4%
tfp, ArI (1.2 equiv, 25 °C, 1 h).
c
6
Scheme 4. Reversal regioselective zincation of chromone (6) by
Lewis acid additions and subsequent iodolysis.
14f
85%d
7
8
9
14g
14h
14i
77%d
93%e
83%e
In order to provide additional support for our mechanistic picꢀ
ture in Scheme 1, we have added the Lewis acid MgCl2 to
TMPZnClꢁLiCl (4). This completely inverts the regioselectivity of
zincation, providing 2ꢀiodoꢀchromone (15a) after iodolysis. A
similar selectivity reversal was achieved by adding as Lewis acid,
BF3ꢁOEt2 affording after iodolysis 15a (Scheme 4).
a
b
Yield of isolated, analytically pure product.
Obtained after
c
transmetalation with CuCNꢁ2LiCl (1.2 equiv, ꢀ40 °C, 30 min). Obꢀ
tained by using 2% Pd(dba)2, 4% P(2ꢀfuryl)3,25 ArI (1.2 equiv, 25 °C,
1 h). Obtained by using 2% Pd(OAc)2, 4% SPhos,26 ArBr (48 h, 50
d
e
Scheme 5. Selective metalation of N-methyl-4-quinolone (7) and
subsequent reaction with electrophiles.
°C). Obtained by Negishi crossꢀcoupling using 2% Pd(OAc)2, 4%
XantPhos,27 ArBr (48 h, 50 °C).
Scheme 2. Preparation of C(2) substituted chromones using
TMP2Zn·2MgCl2·2LiCl (5) and subsequent reaction with electro-
philes.
a
b
I2 (1.2 equiv, 25 °C, 15 min); Obtained after transmetalation with
CuCNꢁ2LiCl (1.2 equiv, ꢀ40 °C, 30 min); 2% Pd(dba)2, 4% tfp, ArI
(1.2 equiv, 25 °C, 1 h).
c
a Obtained after transmetalation with CuCNꢁ2LiCl (1.2 equiv, ꢀ40 °C,
30 min); b 2% Pd(dba)2, 4% tfp, ArI (1.2 equiv, 25 °C, 1 h).
A selective zincation at C(2) was also achieved. Thus, the reacꢀ
tion of chromone (6) with TMP2Znꢁ2MgCl2ꢁ2LiCl (5) led to a
regiospecific metalation at C(2), providing the bisꢀheterocyclic
zinc reagent 12, as shown by iodolysis leading to product 15a
(Scheme 2). Similarly, Cuꢀmediated acylation or Pdꢀcatalyzed
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Scheme 8. Preparation of the flavone chrysin (1), isoflavone bio-
chanin A (2) and graveolinine (3).
Our metalation procedure was extended to Nꢀmethylꢀ4ꢀ
quinolone (7). Deprotonation of 7 with TMPZnClꢁLiCl (4) gave
the C(3)ꢀzincated intermediate 10 which after quenching with
various electrophiles led to products 18a-b. Thus, Cuꢀmediated
allylation afforded the desired Nꢀmethylꢀ4ꢀquinolone 18a. Pdꢀ
catalyzed crossꢀcoupling of the zinc reagent 10 provided the aryꢀ
lated quinolone 18b. Inverse zincation regioselectivity is observed
in the presence of MgCl2. Thus, the metalation of 7 with
TMP2Znꢁ2LiClꢁ2MgCl2 (5) gave the C(2)ꢀzincated Nꢀmethylꢀ4ꢀ
quinolone 13 which was reacted in a Negishi crossꢀcoupling reacꢀ
tion providing the product 19 (Scheme 5).
1
2
3
4
5
6
7
8
9
Finally, we examined the functionalization of thiochromone
(20). Theoretical calculations showed that the difference in acidity
of the hydrogens attached to C(2) and C(3) is much higher in
thiochromone (20) than in chromone (6) and Nꢀmethylꢀ4ꢀ
quinolone (7).21 This strong thermodynamic preference for deproꢀ
tonation at C(2) in 20 affects the zincation regioselectivity. Thus,
metalation of 20 with TMPZnClꢁLiCl (4) in THF produced a mixꢀ
ture of C(2) and C(3)ꢀzincated products. The reactivity of the base
4 can be influenced by reducing the solvent polarity. This reduced
polarity might also affect the complexation at the sulfur atom.
Using a less polar solvent mixture (THF:Et2O), it was possible to
completely direct the metalation to C(2).28 The zincation of thioꢀ
chromone (20) with TMPZnClꢁLiCl (4) in THF:Et2O (2:1) gave
the C(2)ꢀzincated intermediate 21. Transmetation with
CuCNꢁ2LiCl and subsequent quenching with PhCOCl led to the
ketone 22a. Pdꢀcatalyzed crossꢀcoupling with pꢀchloroꢀ
iodobenzene gave the thiochromone 22b (Scheme 6).
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(a) 1)TMP2Znꢁ2MgCl2ꢁ2LiCl (5, 1.0 equiv), ꢀ30 °C, 1 h; 2) 2%
Pd(dba)2, 4 % P(2ꢀfuryl)3, PhI (1.2 equiv, 25 °C, 1 h); (b) H2, 20%
Pd/C, EtOH; (c) TMPZnClꢁLiCl (4, 2 equiv), 25 °C, 0.5 h; 2) 2%
Pd(dba)2, 4% P(2ꢀfuryl)3, ArI (1.2 equiv, 25 °C; 1 h) (d) H2, 20%
Pd/C, EtOAc; (e) 1)TMP2Znꢁ2MgCl2ꢁ2LiCl (5, 1.0 equiv), ꢀ20 °C, 48
h; 2) 2% Pd(dba)2, 4 % P(2ꢀfuryl)3, ArI (1.2 equiv, 25 °C, 1 h).
As an application of this metalation methodology, we prepared
several naturally occurring chromones and quinolones, such as
chrysin (1)3 and biochanin A (2),4 starting from the common preꢀ
cursor 2429 Regioselective metalation of the chromone 24 with
TMP2Znꢁ2MgCl2ꢁ2LiCl (5) provided C(2)ꢀzincation. Negishi
crossꢀcoupling with iodobenzene, gave the flavone 25. On the
other hand, metalation of 24 with TMPZnClꢁLiCl (4) led to the
C(3)ꢀzincated intermediate. Subsequent Pdꢀcatalyzed crossꢀ
coupling with pꢀiodoanisole provided isoflavone 26. Removal of
the benzyl protection groups30 gave the natural products chrysin
(1) and biochanin A (2). The quinolone graveolinine (3),5 was
prepared by Negishi crossꢀcoupling of C(2)ꢀzincated quinolone 13
(Scheme 7).
Scheme 6. Products obtained by the zincation of thiochromone 20
with TMPZnCl·LiCl (4) and subsequent reaction with electro-
philes.
We have also briefly studied the metalation of pyrone (27) usꢀ
ing TMPZnClꢁLiCl (4). A selective zincation at position 3 (leadꢀ
ing to 28) was achieved. Quenching with iodine, allyl bromide,
acylation with pivaloyl chloride and crossꢀcoupling with pꢀchloroꢀ
iodobenzene provides the expected products 29a-d.
a Obtained after transmetalation with CuCNꢁ2LiCl (1.2 equiv, ꢀ40 °C,
30 min); b 2% Pd(dba)2, 4% tfp, ArI (1.2 equiv, 25 °C, 1 h).
The preparation of 2,3ꢀdisubstituted thiochromones was readily
achieved. Thus, zincation of 22a with TMPZnClꢁLiCl (4) providꢀ
ed the expected thiochromone, which underwent a Cuꢀmediated
allylation, acylation or palladiumꢀcatalyzed Negishi crossꢀ
coupling furnishing 2,3ꢀdisubstituted thiochromones 23a-c
(Scheme 7).
Scheme 9. Reactions and conditions for the preparation of 3-
substituted pyronones 29a-d.
Scheme 7. Reactions and conditions for the preparation of 2,3-
disubstituted thiochromones 23a-c.
a
b
I2 (1.2 equiv, 25 °C, 15 min); Obtained after transmetalation with
c
CuCNꢁ2LiCl (1.2 equiv, ꢀ40 °C, 30 min); 2% Pd(dba)2, 4% tfp, ArI
(1.2 equiv 25 °C, 1 h).
(a) 1) TMPZnClꢁLiCl (4, 1.2 equiv), THF, ꢀ20 °C, 15 min; 2)
CuCNꢁ2LiCl, ꢀ40 °C, 0.5 h; 3) Ethyl 2ꢀ(bromomethyl)acrylate, ꢀ40
°C, 10 min; (b) 1) TMPZnClꢁLiCl (4), THF, ꢀ20 °C, 15 min; 2)
CuCNꢁ2LiCl, ꢀ40 °C, 30 min; 3) tBuCOCl, ꢀ40 °C to 25 °C, 4h; (c) 1)
TMPZnClꢁLiCl (4), THF, ꢀ20 °C, 15 min; 2) 2% Pd(dba)2, 4% tfp,
ArI (1.2 equiv, 25 °C, 1 h).
In summary, we have shown; that the regioselectivity of zincaꢀ
tion of chromone (6) and Nꢀmethylꢀ4ꢀquinolone (7) can be diꢀ
rected either in C(2) or C(3) depending on the reaction condiꢀ
tions. Thus, the use of TMPZnClꢁLiCl (4) leads to C(3) zincated
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intermediates, whereas the presence of Lewis acids (MgCl2 or
BF3ꢁOEt2) leads to metalation at C(2). For thiochromone (20), the
use of THF:Et2O (2:1) was essential for controlling the regioseꢀ
lectivity of C(2) zincation. Application to the synthesis of naturalꢀ
ly occurring flavone, isoflavone and quinolone has been shown.
Extension of this methodology to related heterocycles is currently
under investigation.
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ACKNOWLEDGMENT We thank the Fonds der Chemischen
Industrie, the European Research Council (ERC) for financial
support. We also thank Chemetall GmbH (Frankfurt) for the genꢀ
erous gift of chemicals.
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SUPPORTING INFORMATION PARAGRAPH Full experiꢀ
mental details, 1H and 13C spectra, computational details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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=
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=
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