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Practical Large-Scale Regioselective Zincation of Chromone Using TMPZnCl·LiCl Triggered by the Presence or Absence of MgCl 2

Lydia Klier, Dorothée Sophia Ziegler, René Rahimoff, Marc Mosrin, and Paul Knochel Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00032 • Publication Date (Web): 22 Mar 2017 Downloaded from http://pubs.acs.org on March 25, 2017

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Organic Process Research & Development

Practical Large-Scale Regioselective Zincation of Chromone Using TMPZnCl·LiCl Triggered by the Presence or Absence of MgCl2 Lydia Klier,a Dorothée S. Ziegler,a René Rahimoff,a Marc Mosrina,b and Paul Knochela,* a

Department Chemie, Ludwig-Maximilians-Universität, Butenandtstrasse. 5-13, 81377 München, Germany Bayer AG, Research & Development, Crop Science, Alfred-Nobel-Strasse 50, Building 6550, 2.08, 40789 Monheim am Rhein, Germany Supporting Information Placeholder b

ABSTRACT: Chromones are efficiently zincated in position C(3) in THF by using the commercially available amide base TMPZnCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl). Additionally, in the presence of the Lewis acid such as MgCl2, zincation using TMPZnCl·LiCl occurs at C(2). These metalation reactions are carried out on a 50 mmol scale and the metalation selectivities have been compared with the corresponding small-scale reactions (2 mmol). The resulting zinc organometallics undergo smooth reactions with various electrophiles, e.g. Pd-catalyzed cross-coupling reactions or Cu-catalyzed acylations or allylations. KEYWORDS: Chromone, TMP-base, Lewis acid, Regioselective metalation

INTRODUCTION Chromones are an important class of natural products that possess useful pharmaceutical properties, such as antineoplastic, antibacterial, and anti-HIV activity.1 Therefore, the functionalization of this heterocyclic scaffold is of considerable interest and has been thoroughly studied in the literature.2 Recently, we found that the presence of an additional Lewis acid like MgCl2 can trigger a regioselectivity switch from position C(3) to C(2) for the zincation of chromone (1) with TMPZnCl·LiCl (2, Scheme 1).3 Using this method, we have prepared a range of C(2) and C(3) functionalized chromones and demonstrated the utility of this metalation method for the synthesis of several natural products. The observed selectivity was rationalized by assuming a coordination of the C(4) carbonyl to the metal base (TMPZnCl·LiCl, 2), followed by an ortho-metalation and the formation of the C(3)-metalated product 3 (pathway a, Scheme 1).4,5 SCHEME 1. Lewis acid-triggered regioselective zincation of chromone.

In the presence of a stronger Lewis acid (MgCl2) than the cation (Zn2+) of the metalating base (TMPZnCl·LiCl, 2), complexation of this Lewis acid was anticipated to occur at the carbonyl group, providing the C(2)-metalated heterocycle 4. This original method was reported for the preparation of small quantities of functionalized chromones (1-2 mmol). Herein we have expanded this metalation procedure to larger scale experiments (50 mmol) using the commercially available reagent TMPZnCl·LiCl (2).4,5

RESULTS AND DISCUSSION The followed metalation conditions for 2 mmol scale were representative.3 Treatment of chromone (2 mmol) with the amide base TMPZnCl·LiCl (2, 1.2 equiv) in THF at 25 °C provides the zincated chromone 3 with a regioselectivity of 4:96 C(2):C(3) as confirmed by GC-analysis of reaction aliquots quenched with iodine (Scheme 2). Full conversion was observed after 15 min reaction time.6 When the reaction was scaled up to 50 mmol, TMPZnCl·LiCl (2, 50 mL, 1.2 equiv) was added over 30 min at 0 °C to a solution of chromone (1, 7.31 g, 50 mmol) in THF (50 mL). The lower reaction temperature and the slow addition rate are necessary to avoid a decrease in regioselectivity presumably caused by an increase of the reaction temperature. After the addition was completed, the reaction mixture was warmed to 25 °C for additional 7 h. A regioselectivity of 2:98 C(2):C(3) and 98% conversion was determined by GC-analysis of reaction aliquots quenched with iodine (Scheme 2).

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SCHEME 2. Regioselective zincation of chromones performed with TMPZnCl·LiCl with or without MgCl2.

Reaction of the resulting C(3)-zincated chromone 3 with various electrophiles generally required longer reaction times for the 50 mmol scale than in the case of the 2 mmol scale (Table 1). Transmetalation of zinc reagent 3 with CuCN·2LiCl (60 mL, 1.2 equiv)7 and subsequent reaction with allyl bromide (7.3 g, 1.2 equiv) or 3,4-difluorobenzoyl chloride (10.6 g, 1.2 equiv) provided the chromone 5b in 91% yield after 12 h or ketone 5c in 60% yield after 48 h, respectively (entries 2b and 3b). Pd-catalyzed Negishi cross-coupling8 using Pd(PPh3)4 (0.6 g, 1 mol %) and bromobenzaldehyde (11.1 g, 1.2 equiv) led to the cross-coupling product 5d after 18 h at 25 °C (83% yield, entry 4b).

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As described in the literature and also in scheme 2, the zincation of chromone (1, 2 mmol) with TMPZnCl·LiCl (2, 1.2 equiv) in the presence of MgCl2 (2.0 equiv) proceeded best at 0 °C, providing full conversion after 1 h and a regioselectivity of C(2):C(3) 97:3. When the reaction was scaled up to 50 mmol, MgCl2 (2.0 equiv, 250 mL, 0.4 M) was added to a solution of chromone (1, 7.3 g, 50 mmol) in THF at 0 °C and stirred for further 30 min. It was observed, that the selectivity for C(2) metalation depends on both the reaction temperature and the amount of MgCl2 in solution. A reaction temperature of –5 °C during the addition of TMPZnCl·LiCl (2, over 30 min) was necessary to avoid a reduced selectivity caused by higher reaction temperatures. We noticed that lower reaction temperatures than–5 °C caused the precipitation of MgCl2, and therefore provided also lower selectivities. After the addition was completed, the reaction mixture was warmed to 0 °C and stirred for further 2 h, leading to full conversion to the zincated species 4 (C(2):C(3) = 92:8). Iodolysis of the zinc reagent provided 2-iodo-chromone (6a) in 80% yield after 2 h at 25 °C (entry 5b, Table 1). Similarly, Cu-mediated acylation with 2-methylbenzoyl chloride (9.2 g, 1.2 equiv) gave the product 6b after 12 h in 81% yield (entry 6b). Pd-catalyzed Negishi cross-coupling of the zinc species 4 with Pd(dba)2 (565 mg, 2 mol %), tfp (465 mg, 4 mol %)9 and ethyl 5-bromofuran2-carboxylate (13.14 g, 1.2 equiv) furnished the expected C(2)substituted chromone 6c in 62% yield (entry 7b).

TABLE 1. Products obtained by the zincation of chromone (1) with TMPZnCl·LiCl (2) and subsequent reaction with electrophiles. entry

scale

metalation conditions

E (1.2 equiv)

reaction conditions

1a

2 mmol

TMPZnCl·LiCl 25 °C, 30 min, THF

I2

25 °C, 15 min

product/ yielda (%)

5a: 80

1b

50 mmol

TMPZnCl·LiCl 0 °C, 7 h, THF

I2

0 °C, 1h then 25 °C, 12 h 5a: 73

2a

2 mmol


25 °C, 2 h 5b: 98b

2b

50 mmol


25 °C, 12 h 5b: 91b

3a

2 mmol


–40 to 25 °C, 12 h 5c: 82b

3b

50 mmol


–50 to 25 °C, 12 h then 25 °C, 36 h 5c: 60b


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4a

2 mmol


25 °C, 12 h 5d: 96c

4b

50 mmol


25 °C, 18 h 5d: 83c

5a

2 mmol

MgCl2, TMPZnCl·LiCl 0 °C, 1 h, THF

I2

25 °C, 15 min 6a: 84

5b

6a

6b

7a

7b

50 mmol

2 mmol

50 mmol

2 mmol

50 mmol


I2

0 °C 1h, then 25 °C, 2 h 6a: 80


–40 to 0 °C, 6 h


–40 to –10 °C, 12 h


25 °C, 2 h


25 °C, 24 h

6b: 98b

6b: 81b

6c: 78d

6c: 62d

of isolated, analytically pure product. bObtained after transmetalation with CuCN·2LiCl (1.2 equiv, –40 °C, 30 min). cObtained by Negishi cross-coupling using Pd(PPh3)4 (2 mol %). dObtained by Negishi cross-coupling using Pd(dba)2 (2 mol %), tfp (4 mol %).

aYield

CONCLUSION To conclude, a practical and scalable process was developed to prepare C(2) or C(3) functionalized chromones on a multigram scale from the readily available starting material chromone. The presence of MgCl2 allows to switch the metalation regioselectivity from the C(3) to the C(2) in both small and large scale reactions, with comparable regioselectivities. Subsequent reaction of the zincated chromone with representative electrophiles provides up to 10 g of the corresponding functionalized chromones.

EXPERIMENTAL SECTION General Information All reactions were carried out under air and moisture exclusion. All glassware was oven-dried (80 °C, 12 h), flame dried in high vacuum (1×10-3 mbar) and backfilled with argon (this procedure was repeated three times). Syringes which were

used to transfer anhydrous solvents or reagents were purged with argon prior to use. THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under argon. Yields refer to isolated yields of compounds estimated to be >95% pure as determined by 1H NMR (25 °C) and capillary GC analysis. NMR spectra were recorded on solutions in deuterated chloroform (CDCl3). Column chromatographical purifications were performed using SiO2 (0.040-0.063 mm, 230-400 mesh ASTM) from Merck. TMP-H and liquid acid chlorides were distilled prior to use. The completion of the metalation reaction was checked by GC analysis of reaction aliquots (reaction aliquots were quenched with 0.2 mL of a 0.5 M I2 solution in dry THF, then NH4Cl (1 mL) and sat. aq. Na2S2O3 solution (1 mL) were added and extracted with diethyl ether (1 mL). Gas chromatography (GC) GC was performed with machines of the Hewlett-Packard 6890 or 5890 series II, using column of type HP 5 (HewlettPackard, 5% phenylmethylpolysiloxane, length: 15 m,



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diameter: 0.25 mm; film thickness: 0.25 µm). The detection was accomplished by using a flame ionization detector. The carrier gas was nitrogen. Alkanes like tetradecane (retention time: 3.080 min) were used as internal standard. The retention time of chromone (1) was 3.154 min. Preparation of TMPZn·LiCl (2) A dry and argon-flushed 1.0-L Schlenk flask, equipped with a magnetic stirring bar and a rubber septum, was charged with 2,2,6,6-tetramethylpiperidine (59.5 mL, 350 mmol) freshly dissolved in THF (350 mL). This solution was cooled to -40 °C, and n-BuLi (2.3 M in hexane, 152.2 mL, 350 mmol) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm up slowly to -10 °C for 1 h. ZnCl2 (1.0 M in THF, 368 mL, 368 mmol, 1.05 equiv) was added dropwise, and the resulting solution was stirred for 30 min at -10 °C and then for 30 min at 25 °C. The solvents were then removed under vacuum, affording a yellowish solid. Freshly distilled THF was then slowly added under vigorous stirring until the salts were completely dissolved. The freshly prepared TMPZnCl·LiCl (2) solution was titrated prior to use at 25 °C with benzoic acid using 4-(phenylazo)diphenylamine as indicator. A concentration of 1.35 M in THF was obtained. Preparation of C(3) Zincated Chromone 3 A dry and argon flushed flask, equipped with a magnetic stirring bar and a rubber septum was charged with chromone (1, 7.3 g, 50 mmol) in dry THF (50 mL). The base TMPZnCl·LiCl (2, 1.2 M in THF, 50 mL, 1.2 equiv) was added drop wise at 0 °C over 30 min, through an addition funnel. The reaction mixture was warmed to 25 °C and stirred for additional 7 h. The completion of the metalation was checked by GC-analysis of reaction aliquots quenched with iodine indicating a regioselectivity of C(2):C(3) = 98:2 and 98% conversion. Preparation of C(2) Zincated Chromone 4 A dry and argon flushed flask, equipped with a magnetic stirring bar and a rubber septum was charged with chromone (1, 7.31 g, 50 mmol) and dry MgCl2 (0.4 M in THF, 250 mL) at 0 °C. The base TMPZnCl·LiCl (2, 1.2 M in THF, 50 mL, 1.2 equiv) was added dropwise at -5 °C over 30 min, through an addition funnel. The reaction mixture was warmed to 0 °C and stirred for additional 2 h. The completion of the metalation was checked by GC-analysis of reaction aliquots quenched with iodine indicating a regioselectivity of C(2):C(3) = 92:8 and full conversion.

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Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We would like to thank the Ludwig-Maximilians-University Munich for financial support. We thank Bayer and Albemarle Corporation (Hoechst-Frankfurt) for the generous gift of chemicals.

REFERENCES (1) (a) Gaspar, A.; Matos, M. J.; Garrido, J.; Uriate, E.; Borges F. Chem. Rev. 2014, 4960-4992. (b) Flavonoids: Chemistry, Biochemistry and Applications; Andersen, O. M., Markham, K. R., Eds.; CRC Press: Boca Raton, FL, 2006. (c) The Science of Flavonoids; Grotewold, E., Ed.; Springer, New York, 2006; pp 213-238. (2) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F.V, Taylor, R. J. K., Black, D. S. C., Eds.; Elsevier, Oxford, UK; 2008, Vol. 7. (3) Klier, L.; Bresser, T.; Nigst, T. A.; Karaghiosoff, K.; Knochel, P. J. Am. Chem. Soc. 2012, 134, 13584-13587. (4) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837-1840. For recent reviews see: (b) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel P. Angew. Chem. 2011, 123, 9968-9999; Angew. Chem., Int. Ed. 2011, 50, 9794-9824. (c) Klatt, T.; Markiewicz, J. T.; Sämann, C.; Knochel, P. J. Org. Chem. 2014, 79, 4253-4269. (5) TMPZnCl·LiCl can be purchased by Albemarle Corporation (Hoechst-Frankfurt) or by Munichem GmbH (Munich, [email protected]) (6) Supporting Information (7) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390-2392. (8) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298-3299. (b) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45, 52235225. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348. (9) dba = trans, trans-10dibenzylideneacetone; tfp = tris-(2furyl)phosphine; (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595. (b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind L. J. Org. Chem. 1994, 59, 5905-5911. (c) Klement, I. Rottländer, M.; Tucker, C. E.; Majid, T. N.; Knochel, P.; Venegas, P.; Cahiez G. Tetrahedron 1996, 52, 72017220.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Full experimental details; GC data; melting points; mass spectra; infrared spectra; 1H and 13C spectra

AUTHOR INFORMATION Corresponding Author *[email protected]


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