Lewis Acid-Triggered Selective Zincation of Chromones, Quinolones

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“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 Downloaded from http://pubs.acs.org on August 3, 2012

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Lewis acid Triggered Selective Zincation of Chromones, Quinolones and Thiochromones. Application to the Preparation of Natural Flavones and Isoflavones** Lydia Klier, Tomke Bresser, Tobias A. Nigst, Konstantin Karaghiosoff, and Paul Knochel*,† †

Department Chemie, Ludwig-Maximilians-Universitaet Muenchen, Butenandtstr. 5-13, Haus F, 81377 Munich,

[email protected]

KEYWORDS: chromone · Lewis acid · metalation · TMP-base · zinc

ABSTRACT: 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. Application to a natural flavone, isoflavone and quinolone is shown. Chromones and quinolones are important classes of natural products,1 which have useful pharmaceutical properties, such as antineoplastic, antibacterial and anti-HIV activity.2 Typical representative natural products are chrysin (1),3 the isoflavone biochanin A (2)4 and the quinolone graveolinine (3).5 Thiochromones, which are not found as natural products, also show useful bioactivities.6,7 Consequently, the functionalization of these heterocyclic scaffolds is of special synthetic importance. The lithiation at position C(3) and position C(2) of the chromone scaffold and further functionalizations have only been briefly described. A good metalation selectivity between position C(2) and C(3) has yet not been achieved.8,9 The lithiation of unsubstituted chromone with TMP-Li (TMP = 2,2,6,6-tetramethylpiperidyl) 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 Pd-catalyzed direct intermolecular alkenylation11 at position C(3) have been disclosed. A selective C(2) lithiation of quinolone with LDA has also been described.12 Recently, we have reported the preparation of new highly chemoselective TMP-bases such as TMPZnCl·LiCl (4)13 and TMP2Zn·2MgCl2·2LiCl (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 Mg- and Zn-TMP-bases and constitute a new class of frustrated Lewis pairs.16 Thus, the metalation regioselectivity of pyridines with TMP-bases was triggered by the presence of BF3·OEt2.17 Also, magnesium salts,18 triorganoboranes19 and catalytic amounts of Sc(OTf)3 20 influence the reactivity 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 N-methyl-quinolone (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 TMPZnCl·LiCl (4) would coordinate at this oxygen leading through the complexinduced proximity effect (CIPE)22 to complexes of type 8 (pathway a, Scheme 1).

Scheme 1. MgCl2-triggered regioselective zincation of chromone (6) and N-methyl-4- quinolone (7).

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 TMP-zinc 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 N-methyl-4quinolone (7) according to Scheme 1. Thus, we have treated chromone (6) with TMPZnCl·LiCl (4), which resulted in a selective zincation at position C(3) to produce the zinc reagent 9. After iodolysis, 3-iodo-chromone (14a) was isolated (entry 1, Table 1). Transmetalation of 9 with CuCN·2LiCl,23 and subsequent reaction with allylic bromides provided the chromones 14b-c (entries 2-3). The reaction with pivaloyl chloride afforded the expected ketone 14d (entry 4). Pd-catalyzed Negishi cross-coupling24 with aryl iodides or aryl bromides led to the cross-coupling products 14e-i (entries 5-9). Table 1. Products obtained by the zincation of chromone (6) with TMPZnCl·LiCl (4) and subsequent reaction with electrophiles.

entry

electrophile

1

I2

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14a

yielda

77%

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2

14b

87%b

3

14c

75%b

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Negishi cross-coupling furnished the expected C(2)-substituted chromones 15b-e. 2,3-Disubstituted chromones can be readily prepared by two successive metalation / cross-coupling sequences (Scheme 3). Pd-catalyzed cross-coupling of C(2)-zincated chromone 12 with p-iodobenzotrifluoride afforded first the C(2)-substituted flavone 16 (Scheme 3) and then the 2,3-disubstituted chromone 17 after treatment with TMPZnCl·LiCl (4) and subsequent Negishi crosscoupling reaction. Scheme 3. Reagents and conditions for the preparation of the bisfunctionalized chromone 17.

4

5

tBuCOCl

14d

74%b

14e

90%

(a) 1) TMP2Zn·2MgCl2·2LiCl (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) TMPZnCl·LiCl (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).

14f

85%d

Scheme 4. Reversal regioselective zincation of chromone (6) by Lewis acid additions and subsequent iodolysis.

14g

77%d

14h

93%e

14i

e

c

6

7

8

9

83%

a

Yield of isolated, analytically pure product. b Obtained after transmetalation with CuCN·2LiCl (1.2 equiv, -40 °C, 30 min). c Obtained by using 2% Pd(dba)2, 4% P(2-furyl)3,25 ArI (1.2 equiv, 25 °C, 1 h). d Obtained by using 2% Pd(OAc)2, 4% SPhos,26 ArBr (48 h, 50 °C). e Obtained by Negishi cross-coupling using 2% Pd(OAc)2, 4% XantPhos,27 ArBr (48 h, 50 °C).

In order to provide additional support for our mechanistic picture in Scheme 1, we have added the Lewis acid MgCl2 to TMPZnCl·LiCl (4). This completely inverts the regioselectivity of zincation, providing 2-iodo-chromone (15a) after iodolysis. A similar selectivity reversal was achieved by adding as Lewis acid, BF3·OEt2 affording after iodolysis 15a (Scheme 4). Scheme 5. Selective metalation of N-methyl-4-quinolone (7) and subsequent reaction with electrophiles.

Scheme 2. Preparation of C(2) substituted chromones using TMP2Zn·2MgCl2·2LiCl (5) and subsequent reaction with electrophiles.

a

I2 (1.2 equiv, 25 °C, 15 min); b Obtained after transmetalation with CuCN·2LiCl (1.2 equiv, -40 °C, 30 min); c 2% Pd(dba)2, 4% tfp, ArI (1.2 equiv, 25 °C, 1 h). a

A selective zincation at C(2) was also achieved. Thus, the reaction of chromone (6) with TMP2Zn·2MgCl2·2LiCl (5) led to a regiospecific metalation at C(2), providing the bis-heterocyclic zinc reagent 12, as shown by iodolysis leading to product 15a (Scheme 2). Similarly, Cu-mediated acylation or Pd-catalyzed

Obtained after transmetalation with CuCN·2LiCl (1.2 equiv, -40 °C, 30 min); b 2% Pd(dba)2, 4% tfp, ArI (1.2 equiv, 25 °C, 1 h).

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Our metalation procedure was extended to N-methyl-4quinolone (7). Deprotonation of 7 with TMPZnCl·LiCl (4) gave the C(3)-zincated intermediate 10 which after quenching with various electrophiles led to products 18a-b. Thus, Cu-mediated allylation afforded the desired N-methyl-4-quinolone 18a. Pdcatalyzed cross-coupling of the zinc reagent 10 provided the arylated quinolone 18b. Inverse zincation regioselectivity is observed in the presence of MgCl2. Thus, the metalation of 7 with TMP2Zn·2LiCl·2MgCl2 (5) gave the C(2)-zincated N-methyl-4quinolone 13 which was reacted in a Negishi cross-coupling reaction providing the product 19 (Scheme 5). 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 N-methyl-4quinolone (7).21 This strong thermodynamic preference for deprotonation at C(2) in 20 affects the zincation regioselectivity. Thus, metalation of 20 with TMPZnCl·LiCl (4) in THF produced a mixture 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 thiochromone (20) with TMPZnCl·LiCl (4) in THF:Et2O (2:1) gave the C(2)-zincated intermediate 21. Transmetation with CuCN·2LiCl and subsequent quenching with PhCOCl led to the ketone 22a. Pd-catalyzed cross-coupling with p-chloroiodobenzene gave the thiochromone 22b (Scheme 6). Scheme 6. Products obtained by the zincation of thiochromone 20 with TMPZnCl·LiCl (4) and subsequent reaction with electrophiles.

a

Obtained after transmetalation with CuCN·2LiCl (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 2,3-disubstituted thiochromones was readily achieved. Thus, zincation of 22a with TMPZnCl·LiCl (4) provided the expected thiochromone, which underwent a Cu-mediated allylation, acylation or palladium-catalyzed Negishi crosscoupling furnishing 2,3-disubstituted thiochromones 23a-c (Scheme 7).

Scheme 8. Preparation of the flavone chrysin (1), isoflavone biochanin A (2) and graveolinine (3).

(a) 1)TMP2Zn·2MgCl2·2LiCl (5, 1.0 equiv), -30 °C, 1 h; 2) 2% Pd(dba)2, 4 % P(2-furyl)3, PhI (1.2 equiv, 25 °C, 1 h); (b) H2, 20% Pd/C, EtOH; (c) TMPZnCl·LiCl (4, 2 equiv), 25 °C, 0.5 h; 2) 2% Pd(dba)2, 4% P(2-furyl)3, ArI (1.2 equiv, 25 °C; 1 h) (d) H2, 20% Pd/C, EtOAc; (e) 1)TMP2Zn·2MgCl2·2LiCl (5, 1.0 equiv), -20 °C, 48 h; 2) 2% Pd(dba)2, 4 % P(2-furyl)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 precursor 2429 Regioselective metalation of the chromone 24 with TMP2Zn·2MgCl2·2LiCl (5) provided C(2)-zincation. Negishi cross-coupling with iodobenzene, gave the flavone 25. On the other hand, metalation of 24 with TMPZnCl·LiCl (4) led to the C(3)-zincated intermediate. Subsequent Pd-catalyzed crosscoupling with p-iodoanisole 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 cross-coupling of C(2)-zincated quinolone 13 (Scheme 7). We have also briefly studied the metalation of pyrone (27) using TMPZnCl·LiCl (4). A selective zincation at position 3 (leading to 28) was achieved. Quenching with iodine, allyl bromide, acylation with pivaloyl chloride and cross-coupling with p-chloroiodobenzene provides the expected products 29a-d. Scheme 9. Reactions and conditions for the preparation of 3substituted pyronones 29a-d.

Scheme 7. Reactions and conditions for the preparation of 2,3disubstituted thiochromones 23a-c.

a

I2 (1.2 equiv, 25 °C, 15 min); b Obtained after transmetalation with CuCN·2LiCl (1.2 equiv, -40 °C, 30 min); c 2% Pd(dba)2, 4% tfp, ArI (1.2 equiv 25 °C, 1 h).

(a) 1) TMPZnCl·LiCl (4, 1.2 equiv), THF, -20 °C, 15 min; 2) CuCN·2LiCl, -40 °C, 0.5 h; 3) Ethyl 2-(bromomethyl)acrylate, -40 °C, 10 min; (b) 1) TMPZnCl·LiCl (4), THF, -20 °C, 15 min; 2) CuCN·2LiCl, -40 °C, 30 min; 3) tBuCOCl, -40 °C to 25 °C, 4h; (c) 1) TMPZnCl·LiCl (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 zincation of chromone (6) and N-methyl-4-quinolone (7) can be directed either in C(2) or C(3) depending on the reaction conditions. Thus, the use of TMPZnCl·LiCl (4) leads to C(3) zincated

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intermediates, whereas the presence of Lewis acids (MgCl2 or BF3·OEt2) leads to metalation at C(2). For thiochromone (20), the use of THF:Et2O (2:1) was essential for controlling the regioselectivity of C(2) zincation. Application to the synthesis of naturally occurring flavone, isoflavone and quinolone has been shown. Extension of this methodology to related heterocycles is currently under investigation. ACKNOWLEDGMENT We thank the Fonds der Chemischen Industrie, the European Research Council (ERC) for financial support. We also thank Chemetall GmbH (Frankfurt) for the generous gift of chemicals. SUPPORTING INFORMATION PARAGRAPH Full experimental details, 1H and 13C spectra, computational details. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES (1)

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