`of 3-Pyridyl- and Some Arylboronic Acids
`
`Wenjie Li,* Dorian P. Nelson,* Mark S. Jensen,
`R. Scott Hoerrner, Dongwei Cai, Robert D. Larsen, and
`Paul J. Reider
`
`Process Research Department, Merck Research Laboratories,
`P.O. Box 2000, Rahway, New Jersey 07065
`
`wenjie_li@merck.com; dorian_nelson@merck.com
`
`Received April 3, 2002
`
`Abstract: 3-Pyridylboronic acid was prepared in high yield
`and bulk quantity from 3-bromopyridine via a protocol of
`lithium-halogen exchange and “in situ quench”. This tech-
`nique was further studied and evaluated on other aryl
`halides in the preparation of arylboronic acids.
`
`Boronic acids have been widely used for cross-coupling
`reactions in carbon-carbon bond formation.1,2 A typical
`preparation of arylboronic acids involves a reaction
`between an organoborate and an organometal (Li or Mg)
`species, usually prepared by magnesium insertion or
`lithium-halogen exchange of the corresponding aryl
`halides.3 This method has its limitations, however. First,
`it is difficult to apply this method to substrates bearing
`functional groups not compatible with organolithium
`reagents such as esters and nitriles. Second, some
`aryllithium intermediates are intrinsically unstable, as
`in the case of many aromatic heterocycles.4 Alternately,
`arylboronic esters can be prepared from aryl halides or
`aryl triflates via a palladium-catalyzed cross-coupling
`reaction with tetraalkoxydiboron or dialkoxyhydrobo-
`rane.5,6 These methods tolerate a wide range of functional
`groups. However, they are not suitable for large-scale
`synthesis because tetraalkoxydiboron and dialkoxyhy-
`droborane are expensive. In this note we report a revised
`procedure for a high-yielding, reproducible, and scalable
`
`(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
`95, 2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-
`168. (c) Suzuki, A. Pure Appl. Chem. 1994, 66, 213-222. (d) Suzuki,
`A. Pure Appl. Chem. 1991, 63, 419-422.
`(2) For recent developments of the Suzuki reaction and its industrial
`application, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
`2000, 122, 4020-4028. (b) Bei, X.; Turner, H. W.; Weinberg, W. H.;
`Guran, A. S.; Petersen, J. L. J. Org. Chem. 1999, 64, 6797-6803. (c)
`Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413-
`2416. (d) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org.
`Chem. 1999, 64, 3804-3805. (e) Littke, A. F.; Fu, G. C. Angew. Chem.,
`Int. Ed. 1998, 37, 3387-3388. (f) Old, D. W.; Wolfe, J. P.; Buchwald,
`S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (g) Smith, G. B.;
`Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven, T. R. J. Org.
`Chem. 1994, 59, 8151-8156.
`(3) (a) Gerrard, W. The Chemistry of Boron; Academic: New York,
`1961. (b) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316-
`1319. (c) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,
`29, 2631-2634.
`(4) Gilman, H.; Spatz, S. M. J. Org. Chem. 1951, 16, 1485-1494.
`(5) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
`60, 7508-7510. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N.
`Tetrahedron Lett. 1997, 38, 3447-3450.
`(6) (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997,
`62, 6458-6459. (b) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y.
`J. Org. Chem. 2000, 65, 164-168. (c) Baudoin, O.; Gue´nard, D.;
`Gue´ritte, F. J. Org. Chem. 2000, 65, 9268-9271.
`
`5394
`
`J. Org. Chem. 2002, 67, 5394-5397
`
`preparation of 3-pyridylboronic acid (3) via lithium-
`halogen exchange and in situ quench with triisopropyl
`borate. A brief study on the generality of this procedure
`for converting aryl halides to arylboronic acids is also
`reported.
`In our ongoing efforts to synthesize biologically active
`compounds as potential therapeutic agents, we needed
`to introduce a 3-pyridyl moiety onto our target. 3-Py-
`ridylboronic acid (3) was the choice of reagent for this
`transformation, since it is nontoxic and thermally and
`air-stable.7 Although there are commercial sources for
`this compound, it is available in only small quantities,
`and the cost is very high. The existing literature protocol
`for preparing 3-pyridylboronic acid afforded a poor yield
`and required conditions not suitable for scale-up.8 In our
`studies on preparing 3-pyridylboronic acid from 3-bro-
`mopyridine (1), we learned that the order of addition of
`the reagents was the key to a successful preparation.
`When 3-bromopyridine was treated with n-butyllithium
`at -78 °C followed by triisopropyl borate (2), the product
`was isolated in poor yield (20-30%). The “reverse”
`addition procedure, in which 3-bromopyridine was added
`to a solution of n-butyllithium followed by addition of
`triisopropyl borate, gave better yields, but the reaction
`must be run at low temperatures (below -70 °C) in order
`to get consistent results, making it inconvenient for large-
`scale preparation.
`Our next approach was to add n-butyllithium to a
`solution of 3-bromopyridine and triisopropyl borate fol-
`lowed by an acid quench (Scheme 1). This protocol has
`been mentioned before, primarily in patents.9 However,
`very little study and discussion about this technique has
`been described. As it turned out, this sequence of addition
`was superior to those previously described. Not only did
`it consistently afford good yields but it also proved to be
`temperature tolerant, giving the best yields (90-95%) at
`-40 °C and a respectable 80% yield even at 0 °C. This
`was probably because the lithium-halogen exchange on
`3-bromopyridine is much faster than the reaction be-
`tween n-butyllithium and triisopropyl borate. The 3-lithi-
`opyridine intermediate thus generated reacts rapidly
`with the borate in the reaction mixture, thereby mini-
`
`(7) For application of 3-pyridylboronic acid in cross-coupling reac-
`tions, see: (a) Enguehard, C.; Hervet, M.; Allouchi, H.; Debouzy, J.-
`C.; Leger, J.-M.; Gueiffier, A. Synthesis 2001, 4, 595-600. (b) Li, J. J.;
`Yue, W. S. Tetrahedron Lett. 1999, 40, 4507-4510. (c) Bower, J. F.;
`Guillaneux, D.; Nguyen, T.; Wong, P. L.; Snieckus, V. J. Org. Chem.
`1998, 63, 1514-1518. (d) Thompson, W. J.; Jones, J. H.; Lyle, P. A.;
`Thies, J. E. J. Org. Chem. 1988, 53, 2052-2055. (e) Juneja, R. K.;
`Robinson, K. D.; Johnson, C. P.; Atwood, J. L. J. Am. Chem. Soc. 1993,
`115, 3818-3819.
`(8) Fischer, F. C.; Havinga, E. Rec. Trav. Chim. 1965, 84, 439-440.
`(9) (a) DeCamp, A. E.; Grabowski, E. J. J.; Huffman, M. A.; Xavier,
`L. C.; Ho, G.-J.; Mathre, D. J.; Yasuda, N. Preparation of 2-Aryl
`Carbapenems. PCT Int. Appl. WO 9531461, 1995. (b) DeCamp, A.;
`Dolling, U. H.; Li, Y.; Rieger, D. L.; Yasuda, N.; Xavier, L. C. Boron
`Containing Intermediates Useful in the Preparation of Carbapenems.
`U.S. Patent 5338875, 1994. (c) Yasuda, N.; Huffman, M. A.; Ho, G.-J.;
`Xavier, L. C.; Yang, C.; Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress, M.
`H.; Rieger, D. L.; Karady, S.; Sohar, P.; Abramson, N. L.; DeCamp, A.
`E.; Mathre, D. J.; Douglas, A. W.; Dolling, U.-H.; Grabowski, E. J. J.;
`Reider, P. J. J. Org. Chem. 1998, 63, 5438-5446. (d) Singh, A.; Chen,
`C.-K.; Grosso, J. A.; Delaney, E. J.; Wang, X.; Polniaszek, R. P.;
`Thottathil, J. K. Preparation of Isoxazolyl Biphenylsulfonamides from
`Arylsulfonylboronic Acids, Haloarenes, and Aminoisoxazoles. PCT Int.
`Appl. WO 0056685, 2000.
`
`10.1021/jo025792p CCC: $22.00 © 2002 American Chemical Society
`Published on Web 06/13/2002
`
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`
`SCHEME 1
`
`SCHEME 2
`
`mizing the chance for 3-lithiopyridine to undergo unde-
`sired side reactions. The product was isolated by crystal-
`lization from acetonitrile in the form of boroxin 4.10 The
`optimized procedure was easily scaled up to produce 1
`kg of crystalline boroxin 4, which functioned very well
`in a palladium-catalyzed cross-coupling reaction with aryl
`halides. The characterization of boroxin 4 was difficult,
`however, due to the presence of varying amounts of
`hydrates. Therefore, boroxin 4 was converted to its
`pinacol ester 5, which was fully characterized.11
`To study the general scope of this “in situ quench”
`protocol, we applied it to several other aryl halides in
`the preparation of arylboronic acids (Scheme 2). The
`yields were compared to those observed using the tradi-
`tional sequential addition method in which aryl halides
`were treated with n-butyllithium followed by addition of
`the borate.12 As shown in Table 1, the in situ quench
`procedure gave better yields in several heterocyclic
`systems (entries 1-4). This method also worked better
`in the presence of functional groups that are sensitive to
`organolithium species (entries 7-9). It could be assumed
`that the aryllithium species generated from these sub-
`strates either were labile or might undergo side reactions.
`In the in situ quench procedure, the aryllithium species
`
`(10) (a) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996, 37, 3097-3098.
`(b) Mohri, S.-I.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997, 62,
`7072-7073.
`(11) During the preparation of this manuscript, a nonaqueous
`workup procedure for the preparation of arylboronic esters was
`reported: Wong, K.-T.; Chien, Y.-Y.; Liao, Y.-L.; Lin, C.-C.; Chou, M.-
`Y.; Leung, M.-K. J. Org. Chem. 2001, 67, 1041-1044.
`(12) General Procedure for the Sequential Addition Method.
`A 50 mL round-bottomed flask equipped with a temperature probe, a
`magnetic stirrer, and a septum was charged with toluene (16 mL) and
`THF (4 mL) and put under a nitrogen atmosphere. The flask was
`charged with aryl halide (10 mmol). The solution was cooled to -70
`°C using a dry ice/acetone bath. n-Butyllithium (2.5 M in hexanes, 4.8
`mL, 12 mmol) was added dropwise via a syringe pump over 1 h. After
`the mixture was stirred for an additional 0.5 h, triisopropyl borate
`(2.8 mL, 12 mmol) was added while the temperature was held at -70
`°C. The acetone/dry ice bath was then removed, and the reaction
`mixture was allowed to warm to -20 °C before a 2 N HCl solution (10
`mL) was added. When the mixture reached room temperature, it was
`transferred to a 100 mL separatory funnel and the layers were
`separated. The organic layer was assayed by HPLC and the yield was
`determined by comparison with a standard solution of authentic
`product.
`(13) (a) Dack, K. V.; Whitlock, G. A. Preparation of N-hydroxytet-
`rahydropyridylsulfonylacetamides and related compounds as matrix
`metalloprotease inhibitors. PCT Int. Appl. WO 9929667, 1999. (b)
`Gronowitz, S.; HO‹ rnfeldt, A.-B.; Kristjansson, V.; Musil, T. Chem. Scr.
`1986, 26, 305-309.
`
`would be quenched by borate immediately after they were
`formed and, therefore, gave boronic acids in good yields.
`In contrast, the sequential addition method gave better
`yield in entries 10-13. This may indicate that these
`aryllithium species were relatively stable, so the sequen-
`tial addition of borate had no adverse effect. In fact, in
`entries 10-13 significant amounts of unreacted aryl
`bromides were observed in the in situ quench method,
`whereas the sequential addition method consumed all the
`aryl bromides. This suggests that the generation of the
`aryllithium with these substrates was relatively slow,
`therefore allowing n-butyllithium to react competitively
`with triisopropyl borate.
`In conclusion, the revised procedure for lithium-
`halogen exchange with in situ quench with borate offers
`an efficient alternative for preparing some arylboronic
`acids from corresponding aryl halides, especially in
`substrates that are sensitive to organolithium species.
`
`Experimental Section
`General. All reactions were performed under nitrogen. THF
`and toluene were dried using 4 Å molecular sieves overnight.
`Commercially available reagents were used without further
`purification.
`3-Pyridylboroxin (4). A 1 L, three-necked flask equipped
`with a temperature probe, an overhead stirrer, and a septum
`was charged with toluene (320 mL) and THF (80 mL) and put
`under a nitrogen atmosphere. The flask was charged with
`triisopropyl borate (55.4 mL, 240 mmol) and 3-bromopyridine
`(19.3 mL, 200 mmol). The mixture was cooled to -40 °C using
`a dry ice/acetone bath. n-Butyllithium (2.5 M in hexanes, 96 mL,
`240 mmol) was added dropwise via a syringe pump over 1 h,
`and the mixture was stirred for an additional 0.5 h while the
`temperature was held at -40 °C. The acetone/dry ice bath was
`removed, and the reaction mixture was then allowed to warm
`to -20 °C before a 2 N HCl solution (200 mL) was added. When
`the mixture reached room temperature, it was transferred to a
`1 L separatory funnel and the aqueous layer (pH (cid:25) 1) was cut
`into a 500 mL Erlenmeyer flask. While the aqueous layer was
`stirred, its pH was adjusted to 7 using a 5 N NaOH solution ((cid:25)
`30 mL). A white solid product precipitated as the pH approached
`7. This mixture was then saturated with 50 g of NaCl, trans-
`ferred to a 1 L separatory funnel, and extracted three times with
`THF (250 mL portions). The combined THF extracts were
`evaporated in vacuo to provide a solid. The solid was taken up
`in acetonitrile (80 mL) for crystallization. The resulting slurry
`was heated to 70 °C, stirred for 30 min, and allowed to cool
`slowly to room temperature before it was cooled to 0 °C using
`an ice bath. After the slurry was stirred at 0 °C for 30 min, the
`solid was collected on a fritted glass funnel. The solid was
`washed with cold acetonitrile (5 °C, 15 mL) and dried under
`vacuum to afford 19.61 g of white solid. A satisfactory melting
`point for this solid could not be obtained. 1H NMR (400 MHz,
`CD3OD) (cid:228) 8.62 (br, 1 H), 8.56-8.54 (m, 1 H), 8.45 (d, 1 H, J)
`7.2 Hz), 7.74 (t, 1 H, J ) 6.6 Hz). Anal. Calcd for C15H12B3O3N3(cid:226)
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`TABLE 1. Preparation of Arylboronic Acids from Aryl Halides
`
`a Yields were determined by HPLC assay. b Products show 1H NMR data and HPLC retention times consistent with commercial authentic
`samples (entries 1, 3, and 5-13). c Product shows 1H NMR data consistent with the literature (ref 13a). d Product shows 1H NMR data
`consistent with the literature (ref 13b). e In this entry, 2 equiv of n-butyllithium was used.
`
`0.5H2O: C, 55.65; H, 4.05; N, 12.98. Found: C, 55.51; H, 4.10;
`N, 12.88. The yield based on this formula was 91%.
`3-Pyridylboronic Acid Pinacol Ester (5). A 1 L three-
`necked flask equipped with a stir bar, a nitrogen inlet adapter,
`and a Dean-Stark trap with a condenser was charged with
`3-pyridylboroxin 4(cid:226)0.5H2O (10.0 g, 30.8 mmol), pinacol (13.5 g,
`114 mmol), and toluene (400 mL). The solution was heated with
`a 120 °C oil bath and refluxed using a Dean-Stark apparatus
`for 2.5 h. The reaction was finished when the solution went from
`cloudy white to clear. The solution was then concentrated in
`vacuo to provide a solid. This solid was taken up in cyclohexane
`(50 mL) and crystallized by holding the suspension at 85 °C for
`30 min and then allowing the temperature to slowly return to
`room temperature. The slurry was filtered, and the solid was
`washed with cyclohexane (10 mL) and dried under vacuum to
`afford 15.39 g of 5 as a white solid (81% from 4, 72% from
`3-bromopyridine). Mp: 103-106 °C. 1H NMR (400 MHz, CDCl3)
`(cid:228) 8.95 (br, 1 H), 8.67 (dd, 1 H, J ) 1.8, 4.9 Hz), 8.06 (dt, 1 H, J
`) 1.8, 7.5 Hz), 7.29-7.26 (m, 1 H), 1.36 (s, 12 H). 13C NMR (100
`MHz, CDCl3) (cid:228) 155.4, 151.9, 142.3, 124.0, 123.1, 84.2, 24.9. Anal.
`Calcd for C11H16BO2N: C, 64.43; H, 7.86; N, 6.83; B, 5.27.
`Found: C, 64.16; H, 7.72; N, 6.62; B, 5.35.
`
`5396 J. Org. Chem., Vol. 67, No. 15, 2002
`
`General In Situ Quench Procedure for the Preparation
`of Arylboronic Acids. A 50 mL round-bottomed flask equipped
`with a temperature probe, a magnetic stirrer, and a septum was
`charged with toluene (16 mL) and THF (4 mL) and put under a
`nitrogen atmosphere. The flask was charged with triisopropyl
`borate (2.8 mL, 12 mmol) and aryl halide (10 mmol). The mixture
`was cooled to -70 °C using a dry ice/acetone bath. n-Butyl-
`lithium (2.5 M in hexanes, 4.8 mL, 12 mmol) was added dropwise
`via a syringe pump over 1 h, and the mixture was stirred for an
`additional 0.5 h while the temperature was held at -70 °C. The
`acetone/dry ice bath was removed, and the reaction mixture was
`then allowed to warm to -20 °C before a 2 N HCl solution (10
`mL) was added. When the mixture reached room temperature,
`it was transferred to a 100 mL separatory funnel and the layers
`were separated. Both the organic and aqueous layers were
`assayed by HPLC, and the yield was determined by comparison
`with a standard solution of authentic product.
`Isolation for Entries 1, 2, and 4. The aqueous layers were
`neutralized to pH (cid:25) 7 using a 5 N NaOH solution followed by
`extraction with THF ((cid:2)3). The combined THF extracts were
`evaporated in vacuo to provide solids, which were recrystallized
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`from acetonitrile. The recrystallized products gave satisfactory
`1H NMR spectra.
`Isolation for Entries 3 and 5-13. The organic layers were
`evaporated in vacuo to provide solids, which were recrystallized
`from acetonitrile. The recrystallized products gave satisfactory
`1H NMR spectra.
`
`Acknowledgment. We thank Prof. Barry Trost and
`Dr. Nobuyoshi Yasuda for their helpful discussions and
`suggestions. We also thank Ms. Vicky Vydra for melting
`point data.
`JO025792P
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