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On the deprotonation of 3,5-dichloropyridine using lithium bases: in situ infrared spectroscopic studies
Tetrahedron 61 (2005) 3245–3249
On the deprotonation of 3,5-dichloropyridine using lithium bases: in situ infrared spectroscopic studies Elodie Weymeels, Hac¸an Awad, Laurent Bischoff, Florence Mongin,* Franc¸ois Tre´court, Guy Que´guiner* and Francis Marsais Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan Cedex, France Received 28 July 2004; revised 27 September 2004; accepted 15 October 2004 Available online 21 November 2004
Abstract—Deprotonation of 3,5-dichloropyridine using LTMP and BuLi was monitored in real time by infrared spectroscopy. It appeared that the substrate was rapidly deprotonated. Transient structures between the substrate and the lithio derivative were detected. The absorbances recorded for the lithio derivative showed that the structures obtained using LTMP and BuLi were similar. When BuLi was used to deprotonate, a complete deuteration of the lithio derivative was noted upon quenching with D2O. The latter did not allow the quantification of the lithio derivative when LTMP was used, since only partial deuteration was observed. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Interest in p-deficient heteroaromatics (pyridine, quinoline, diazines etc.) either for pharmaceuticals or as building blocks for various applications within materials science and supramolecular chemistry has led to extensive efforts devoted to a variety of synthetic methodologies.1 Notably, the uses of organolithium compounds formed through deprotonation allow many functionalizations.2 Yet, due to uncertainties related to aggregation states and the structures of the reactive species, reaction sequences that proceed via organolithium species are among the most difficult to characterize.3 Over the last years, only some studies of metallations by in situ infrared spectroscopy were developed,4 often concerning aliphatic substrates. For IR spectroscopy monitorings, a strongly absorbing group (typically, a C]O group) is often preferred. Nevertheless, in order to extend the use of this technique, we have attempted the real time monitoring of commercial aromatic substrates deprotonations.
Metallation of 3,5-dichloropyridine at C4 with LDA is known to be facile in THF.2b For IR monitorings, we used LTMP and BuLi. The spectra were recorded with a ReactIRe 4000 fitted with an immersible DiComp ATR probe.5 The experiments were conducted as follows: (1) THF was introduced and cooled to K75 8C; (2) the spectral baseline was reset to zero and the spectra recording was started; (3) the substrate was introduced; (4) the base was added dropwise; and (5) the deuteriolysis was effected after complete deprotonation.
In this paper, we provide an investigation into the kinetics and mechanism of the 3,5-dichloropyridine deprotonation using LTMP (thermodynamic or kinetic control) and BuLi (kinetic control).
Keywords: Metallation; Pyridines; In situ IR; Mechanism; Deuteration. * Corresponding authors. Tel.: C33 2 35 52 24 82; fax: C33 2 35 52 29 62; e-mail addresses: [email protected]; [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.10.098
The absorption bands associated with 3,5-dichloropyridine (695, 811, 884, 1011, 1108, 1208, 1305, 1401, 1420, 1559, 3046 and 3123 cmK1; Fig. 1) instantly decreased upon addition of the base as 3,5-dichloropyridine was consumed. They were rapidly replaced by the absorbance associated with the aryllithium species. By comparing the absorbance bands obtained using LTMP (Fig. 1(a)) and BuLi (Fig. 1(b)), one can realize that two values (753 and 1007 cmK1) out of the three attributed unambiguously to 3,5-dichloro-4-pyridyllithium are identical, the third (1139 cmK1 using LTMP and 1143 cmK1 using BuLi) differing little. This slight difference between both structures could be due to different ligands on lithium (THF, 2,2,6,6-tetramethylpiperidine or LTMP); the presence of the ring nitrogen could complicate even more things.6 The profiles obtained for the consumption of 3,5-dichloropyridine versus time showed that 1.25 equiv of LTMP were
3246
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
Figure 1. Progression of the reaction between 3,5-dichloropyridine and (a) LTMP or (b) BuLi, and subsequent deuteriolysis.
required to allow a complete deprotonation (Fig. 2(a)), which was ensured using 1 equiv of BuLi (Fig. 2(b)). A competitive formation of a complex between the aryllithium generated and LTMP could be responsible for this observation.7,8 Other peaks are of particular interest (749, 788, 1000, 1139 and 1532 cmK1 using LTMP (Figs. 1(a) and 3), and 749, 1000, 1050 and 1139 cmK1 using BuLi (Fig. 1(b))): they initially grew upon addition of the base, but immediately
disappeared to be replaced by the absorbance associated with the aryllithium species. Since various examples demonstrate dominance of a complex-induced proximity effect (CIPE)9 process in the metallation reactions with alkyllithiums and, rarely, with lithium dialkylamides, we wondered if such transient structures could consist of prelithiation complexes (formed through interaction between the substrate and the lithium of the base before deprotonation).4c This possibility could be
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
3247
Figure 2. Consumption of 3,5-dichloropyridine versus time using (a) LTMP or (b) BuLi at 811 cmK1.
discarded since a careful analysis of the spectra showed 2,2,6,6-tetramethylpiperidine (N–H at 3316 cm K1) appeared at the same time as the transient structure, when LTMP was used.
The formation of a transient 2-lithiopyridine was next considered.10 In this case, deprotonation of 4-deuterated 3,5-dichloropyridine would have afforded some 2-deuterated derivative. This possibility can also be ruled out since
Figure 3. Progression of the reaction between 3,5-dichloropyridine and (a) LTMP or (b) BuLi, and subsequent deuteriolysis.
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E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
treating the 4-deuterated substrate successively with LTMP or BuLi and 3,4,5-trimethoxybenzaldehyde did not afford the 2-deuterated compounds. A product functionalized at C4 without deuterium at C2 was obtained using BuLi. The existence of identical absorption values for the transient structures detected using LTMP and BuLi (749, 1000 and 1139 cmK1), as well as wavenumbers close to those of the lithio derivatives, suggest a rapid change in the aggregation state from a transient monomer to a dimer structure. It is known that phenyllithium is a mixture of dimer and monomer in THF;11 concerning pyridyllithiums, such studies were not reported (Scheme 1).
Scheme 3.
3. Conclusion
Scheme 1.
The deuteriolysis was effected after complete deprotonation. Nevertheless, when LTMP (2 equiv) was used, the IR monitoring of the trapping step evidenced the formation of both 3,5-dichloropyridine (1559 cmK1) and 3,5-dichloro-4deuteriopyridine (1544 cmK1). This was confirmed by NMR analysis, which showed that the product obtained incorporated only 70% of deuterium. On the other hand, the reaction carried out with BuLi (1 equiv) afforded the completely 4-deuterated compound (Fig. 3). A similar observation was described by Brandsma, when deprotonating quinoline or isoquinoline with equimolar quantities of potassium tert-butoxide and LDA in THF-hexane with HMPA as a co-solvent.12 A H-bonded complex between the lithio derivative and 2,2,6,6-tetramethylpiperidine (Scheme 2) could be envisaged as responsible for the partial deuteration observed, analogous to that observed several years ago by Seebach between lithium enolates and secondary amines.13 Nevertheless, chelation between the aryllithium and 2,2,6,6tetramethylpiperidine is unlikely and a more plausible explanation can be claimed. Trost proposed a competition between the hydrogen–deuterium exchange of the N–H and the organolithium trapping during deuteriolysis.14 In our case, the IR spectra showed the disappearance of the N–H band at 3316 cmK1 associated with 2,2,6,6-tetramethylpiperidine upon addition of D2O. It results that HOD obtained in this way could compete with D2O in the quenching of the pyridyllithium (Scheme 3).
It is worth noting that even in the absence of a strongly absorbing group, deprotonation reactions can be monitored by in situ infrared spectroscopy. When treated with LTMP or BuLi, it appeared that 3,5-dichloropyridine was instantly deprotonated. Without monitoring, reaction conditions (time, temperature, number of equivalents) are often overestimated, which can be a source of degradation and/or competitive reactions. In addition, the monitoring furnished information on the contents of the reaction mixture. Transient structures between the substrate and the lithio derivative were detected and attributed to a monomeric pyridyllithium structure. The absorbances recorded for the lithio derivative showed similar structures obtained using LTMP and BuLi. Finally, we gained in knowledge about the trapping step. When BuLi was used to deprotonate, a complete deuteration of the lithio derivative was noted. On the other hand, D2O proved to react with HTMP giving HOD, since only partial deuteration was observed.
4. Experimental 4.1. General The 1H NMR and 13C NMR spectra were recorded with a 300 MHz spectrometer. THF was distilled from
Scheme 2. To simplify matters, 3,5-dichloro-4-pyridyllithium was shown as a monomer.
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
benzophenone/Na. The water content of the solvents was estimated to be lower than 45 ppm by the modified Karl Fischer method.15 Metallation reactions were carried out under dry nitrogen. Deuterium incorporation was determined from the 1H NMR integration values. After the reaction, hydrolysis, and neutralization, the aqueous solution was extracted several times with CH2Cl2. The organic layer was dried over Na2SO4, the solvents were evaporated under reduced pressure, and unless otherwise noted, the crude compound was chromatographed on a silica gel column (the eluent is given in the product description). 4.2. IR spectroscopic analyses, typical procedure Samples were recorded using a ReactIRe 4000 from ASI Applied Systems fitted with an immersible DiComp ATR probe optimized for maximum sensitivity. The spectra were acquired in 64 scans per spectrum at a gain of 1 and a resolution of 8 using system ReactIRe 2.21 software. A representative reaction was carried out as follows: The IR probe was inserted through a nylon adapter and O-ring seal into an oven-dried, cylindrical adjustable-volume ReactIRe microcell16 fitted with a magnetic stir bar under N2 atmosphere. The flask was charged with THF (4 mL) and cooled at K75 8C before the recording of a background spectrum (1024 scans). IR spectra were collected at 2 min intervals over the course of the reaction. 3,5-Dichloropyridine (0.25 g, 1.7 mmol) was introduced after two acquisitions. BuLi was added after the sixth (0.85 mmol) and the seventh (0.85 mmol) acquisition at the same temperature. The mixture was quenched by an excess of D2O (0.5 mL) after the 18th acquisition. 4.3. a-(3,4,5-Trimethoxyphenyl)-3,5-dichloro-4pyridinemethanol A solution of 4-deuterio-3,5-dichloropyridine (0.26 g, 1.7 mmol) in THF (4 mL) was cooled at K75 8C and treated with BuLi (1.7 mmol). After 1 h at K75 8C, the mixture was quenched with 3,4,5-trimethoxybenzaldehyde. Addition of water saturated with NH4Cl (0.5 mL) was effected after 1 h to give 0.23 g (39%) of a-(3,4,5trimethoxyphenyl)-3,5-dichloro-4-pyridinemethanol (eluent: CH2Cl2): white solid, mp 107–108 8C; 1H NMR (CDCl3) d 3.60 (broad s, 1H), 3.78 (s, 6H), 3.82 (s, 3H), 6.48 (d, 1H, JZ6.8 Hz), 6.53 (s, 2H), 8.49 (s, 2H); 13C NMR (CDCl3) d 56.0 (2C, p), 60.8 (p), 71.3 (t), 102.7 (2C, t), 131.8 (q), 135.2 (q), 137.3 (q), 145.8 (q), 148.5 (t), 153.1 (q); IR (KBr) n 3413, 3000, 2939, 2837, 2249, 1593, 1507, 1462, 1417, 1394, 1329, 1235, 1128, 1099, 1004, 732, 711, 641. Anal. calcd for C15H15Cl2NO4 (344.20): C, 52.34; H, 4.39; N, 4.07. Found: C, 51.95; H, 4.02; N, 3.84%.
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References and notes 1. Katritzky, A. R.; Rees, C. W. In Boulton, A. J., McKillop, A., Eds.; Comprehensive Heterocyclic Chemistry; Pergamon: New York, 1984; Vol. 2. 2. (a) Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187–304. (b) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059–4090. (c) Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489–4505. 3. Concerning NMR studies, see for instance: (a) Bauer, W.; Schleyer, P. V. R. Adv. Carbanion Chem. 1992, 1, 89–175. (b) Gu¨nther, H. J. Braz. Chem. Soc. 1999, 10, 241–262. 4. See for example: (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539–3540. (b) Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452–2458. (c) Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 2001, 123, 4919–4927. (d) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411–14424. 5. ASI Applied Systems, Mettler Toledo. 6. See for example: Leung, W.-P.; Weng, L.-H.; Wang, R.-J.; Mak, T. C. W. Organometallics 1995, 14, 4832–4836. 7. Concerning the formation of complexes between aryllithiums and lithium amides, see: Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. J. Org. Chem. 1998, 63, 8266–8275. 8. Concerning the aggregation of LTMP in solution, see: Wiedemann, S. H.; Ramirez, A.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 15893–15901. 9. (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356–363. (b) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43, 2206–2225. 10. Gros, P.; Choppin, S.; Fort, Y. J. Org. Chem. 2003, 68, 2243–2247. 11. Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg, W. S.; ¨ .; Dykstra, R. R.; Phillips, N. H. J. Am. Gudmundsson, B.O Chem. Soc. 1998, 120, 7201–7210 and references cited. 12. Verbeek, J.; George, A. V. E.; de Jong, R. L. P.; Brandsma, L. J. Chem. Soc., Chem. Commun. 1984, 257–258. 13. Laube, T.; Dunitz, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1373–1393. 14. Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1–360. 15. Bizot, J. Bull. Soc. Chim. Fr. 1967, 151. 16. Kelly, T. R.; Silva, R. A.; Finkenbeiner, G. Tetrahedron Lett. 2000, 41, 9651–9654.
On the deprotonation of 3,5-dichloropyridine using lithium bases: in situ infrared spectroscopic studies Elodie Weymeels, Hac¸an Awad, Laurent Bischoff, Florence Mongin,* Franc¸ois Tre´court, Guy Que´guiner* and Francis Marsais Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan Cedex, France Received 28 July 2004; revised 27 September 2004; accepted 15 October 2004 Available online 21 November 2004
Abstract—Deprotonation of 3,5-dichloropyridine using LTMP and BuLi was monitored in real time by infrared spectroscopy. It appeared that the substrate was rapidly deprotonated. Transient structures between the substrate and the lithio derivative were detected. The absorbances recorded for the lithio derivative showed that the structures obtained using LTMP and BuLi were similar. When BuLi was used to deprotonate, a complete deuteration of the lithio derivative was noted upon quenching with D2O. The latter did not allow the quantification of the lithio derivative when LTMP was used, since only partial deuteration was observed. q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Interest in p-deficient heteroaromatics (pyridine, quinoline, diazines etc.) either for pharmaceuticals or as building blocks for various applications within materials science and supramolecular chemistry has led to extensive efforts devoted to a variety of synthetic methodologies.1 Notably, the uses of organolithium compounds formed through deprotonation allow many functionalizations.2 Yet, due to uncertainties related to aggregation states and the structures of the reactive species, reaction sequences that proceed via organolithium species are among the most difficult to characterize.3 Over the last years, only some studies of metallations by in situ infrared spectroscopy were developed,4 often concerning aliphatic substrates. For IR spectroscopy monitorings, a strongly absorbing group (typically, a C]O group) is often preferred. Nevertheless, in order to extend the use of this technique, we have attempted the real time monitoring of commercial aromatic substrates deprotonations.
Metallation of 3,5-dichloropyridine at C4 with LDA is known to be facile in THF.2b For IR monitorings, we used LTMP and BuLi. The spectra were recorded with a ReactIRe 4000 fitted with an immersible DiComp ATR probe.5 The experiments were conducted as follows: (1) THF was introduced and cooled to K75 8C; (2) the spectral baseline was reset to zero and the spectra recording was started; (3) the substrate was introduced; (4) the base was added dropwise; and (5) the deuteriolysis was effected after complete deprotonation.
In this paper, we provide an investigation into the kinetics and mechanism of the 3,5-dichloropyridine deprotonation using LTMP (thermodynamic or kinetic control) and BuLi (kinetic control).
Keywords: Metallation; Pyridines; In situ IR; Mechanism; Deuteration. * Corresponding authors. Tel.: C33 2 35 52 24 82; fax: C33 2 35 52 29 62; e-mail addresses: [email protected]; [email protected] 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.10.098
The absorption bands associated with 3,5-dichloropyridine (695, 811, 884, 1011, 1108, 1208, 1305, 1401, 1420, 1559, 3046 and 3123 cmK1; Fig. 1) instantly decreased upon addition of the base as 3,5-dichloropyridine was consumed. They were rapidly replaced by the absorbance associated with the aryllithium species. By comparing the absorbance bands obtained using LTMP (Fig. 1(a)) and BuLi (Fig. 1(b)), one can realize that two values (753 and 1007 cmK1) out of the three attributed unambiguously to 3,5-dichloro-4-pyridyllithium are identical, the third (1139 cmK1 using LTMP and 1143 cmK1 using BuLi) differing little. This slight difference between both structures could be due to different ligands on lithium (THF, 2,2,6,6-tetramethylpiperidine or LTMP); the presence of the ring nitrogen could complicate even more things.6 The profiles obtained for the consumption of 3,5-dichloropyridine versus time showed that 1.25 equiv of LTMP were
3246
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
Figure 1. Progression of the reaction between 3,5-dichloropyridine and (a) LTMP or (b) BuLi, and subsequent deuteriolysis.
required to allow a complete deprotonation (Fig. 2(a)), which was ensured using 1 equiv of BuLi (Fig. 2(b)). A competitive formation of a complex between the aryllithium generated and LTMP could be responsible for this observation.7,8 Other peaks are of particular interest (749, 788, 1000, 1139 and 1532 cmK1 using LTMP (Figs. 1(a) and 3), and 749, 1000, 1050 and 1139 cmK1 using BuLi (Fig. 1(b))): they initially grew upon addition of the base, but immediately
disappeared to be replaced by the absorbance associated with the aryllithium species. Since various examples demonstrate dominance of a complex-induced proximity effect (CIPE)9 process in the metallation reactions with alkyllithiums and, rarely, with lithium dialkylamides, we wondered if such transient structures could consist of prelithiation complexes (formed through interaction between the substrate and the lithium of the base before deprotonation).4c This possibility could be
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
3247
Figure 2. Consumption of 3,5-dichloropyridine versus time using (a) LTMP or (b) BuLi at 811 cmK1.
discarded since a careful analysis of the spectra showed 2,2,6,6-tetramethylpiperidine (N–H at 3316 cm K1) appeared at the same time as the transient structure, when LTMP was used.
The formation of a transient 2-lithiopyridine was next considered.10 In this case, deprotonation of 4-deuterated 3,5-dichloropyridine would have afforded some 2-deuterated derivative. This possibility can also be ruled out since
Figure 3. Progression of the reaction between 3,5-dichloropyridine and (a) LTMP or (b) BuLi, and subsequent deuteriolysis.
3248
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
treating the 4-deuterated substrate successively with LTMP or BuLi and 3,4,5-trimethoxybenzaldehyde did not afford the 2-deuterated compounds. A product functionalized at C4 without deuterium at C2 was obtained using BuLi. The existence of identical absorption values for the transient structures detected using LTMP and BuLi (749, 1000 and 1139 cmK1), as well as wavenumbers close to those of the lithio derivatives, suggest a rapid change in the aggregation state from a transient monomer to a dimer structure. It is known that phenyllithium is a mixture of dimer and monomer in THF;11 concerning pyridyllithiums, such studies were not reported (Scheme 1).
Scheme 3.
3. Conclusion
Scheme 1.
The deuteriolysis was effected after complete deprotonation. Nevertheless, when LTMP (2 equiv) was used, the IR monitoring of the trapping step evidenced the formation of both 3,5-dichloropyridine (1559 cmK1) and 3,5-dichloro-4deuteriopyridine (1544 cmK1). This was confirmed by NMR analysis, which showed that the product obtained incorporated only 70% of deuterium. On the other hand, the reaction carried out with BuLi (1 equiv) afforded the completely 4-deuterated compound (Fig. 3). A similar observation was described by Brandsma, when deprotonating quinoline or isoquinoline with equimolar quantities of potassium tert-butoxide and LDA in THF-hexane with HMPA as a co-solvent.12 A H-bonded complex between the lithio derivative and 2,2,6,6-tetramethylpiperidine (Scheme 2) could be envisaged as responsible for the partial deuteration observed, analogous to that observed several years ago by Seebach between lithium enolates and secondary amines.13 Nevertheless, chelation between the aryllithium and 2,2,6,6tetramethylpiperidine is unlikely and a more plausible explanation can be claimed. Trost proposed a competition between the hydrogen–deuterium exchange of the N–H and the organolithium trapping during deuteriolysis.14 In our case, the IR spectra showed the disappearance of the N–H band at 3316 cmK1 associated with 2,2,6,6-tetramethylpiperidine upon addition of D2O. It results that HOD obtained in this way could compete with D2O in the quenching of the pyridyllithium (Scheme 3).
It is worth noting that even in the absence of a strongly absorbing group, deprotonation reactions can be monitored by in situ infrared spectroscopy. When treated with LTMP or BuLi, it appeared that 3,5-dichloropyridine was instantly deprotonated. Without monitoring, reaction conditions (time, temperature, number of equivalents) are often overestimated, which can be a source of degradation and/or competitive reactions. In addition, the monitoring furnished information on the contents of the reaction mixture. Transient structures between the substrate and the lithio derivative were detected and attributed to a monomeric pyridyllithium structure. The absorbances recorded for the lithio derivative showed similar structures obtained using LTMP and BuLi. Finally, we gained in knowledge about the trapping step. When BuLi was used to deprotonate, a complete deuteration of the lithio derivative was noted. On the other hand, D2O proved to react with HTMP giving HOD, since only partial deuteration was observed.
4. Experimental 4.1. General The 1H NMR and 13C NMR spectra were recorded with a 300 MHz spectrometer. THF was distilled from
Scheme 2. To simplify matters, 3,5-dichloro-4-pyridyllithium was shown as a monomer.
E. Weymeels et al. / Tetrahedron 61 (2005) 3245–3249
benzophenone/Na. The water content of the solvents was estimated to be lower than 45 ppm by the modified Karl Fischer method.15 Metallation reactions were carried out under dry nitrogen. Deuterium incorporation was determined from the 1H NMR integration values. After the reaction, hydrolysis, and neutralization, the aqueous solution was extracted several times with CH2Cl2. The organic layer was dried over Na2SO4, the solvents were evaporated under reduced pressure, and unless otherwise noted, the crude compound was chromatographed on a silica gel column (the eluent is given in the product description). 4.2. IR spectroscopic analyses, typical procedure Samples were recorded using a ReactIRe 4000 from ASI Applied Systems fitted with an immersible DiComp ATR probe optimized for maximum sensitivity. The spectra were acquired in 64 scans per spectrum at a gain of 1 and a resolution of 8 using system ReactIRe 2.21 software. A representative reaction was carried out as follows: The IR probe was inserted through a nylon adapter and O-ring seal into an oven-dried, cylindrical adjustable-volume ReactIRe microcell16 fitted with a magnetic stir bar under N2 atmosphere. The flask was charged with THF (4 mL) and cooled at K75 8C before the recording of a background spectrum (1024 scans). IR spectra were collected at 2 min intervals over the course of the reaction. 3,5-Dichloropyridine (0.25 g, 1.7 mmol) was introduced after two acquisitions. BuLi was added after the sixth (0.85 mmol) and the seventh (0.85 mmol) acquisition at the same temperature. The mixture was quenched by an excess of D2O (0.5 mL) after the 18th acquisition. 4.3. a-(3,4,5-Trimethoxyphenyl)-3,5-dichloro-4pyridinemethanol A solution of 4-deuterio-3,5-dichloropyridine (0.26 g, 1.7 mmol) in THF (4 mL) was cooled at K75 8C and treated with BuLi (1.7 mmol). After 1 h at K75 8C, the mixture was quenched with 3,4,5-trimethoxybenzaldehyde. Addition of water saturated with NH4Cl (0.5 mL) was effected after 1 h to give 0.23 g (39%) of a-(3,4,5trimethoxyphenyl)-3,5-dichloro-4-pyridinemethanol (eluent: CH2Cl2): white solid, mp 107–108 8C; 1H NMR (CDCl3) d 3.60 (broad s, 1H), 3.78 (s, 6H), 3.82 (s, 3H), 6.48 (d, 1H, JZ6.8 Hz), 6.53 (s, 2H), 8.49 (s, 2H); 13C NMR (CDCl3) d 56.0 (2C, p), 60.8 (p), 71.3 (t), 102.7 (2C, t), 131.8 (q), 135.2 (q), 137.3 (q), 145.8 (q), 148.5 (t), 153.1 (q); IR (KBr) n 3413, 3000, 2939, 2837, 2249, 1593, 1507, 1462, 1417, 1394, 1329, 1235, 1128, 1099, 1004, 732, 711, 641. Anal. calcd for C15H15Cl2NO4 (344.20): C, 52.34; H, 4.39; N, 4.07. Found: C, 51.95; H, 4.02; N, 3.84%.
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References and notes 1. Katritzky, A. R.; Rees, C. W. In Boulton, A. J., McKillop, A., Eds.; Comprehensive Heterocyclic Chemistry; Pergamon: New York, 1984; Vol. 2. 2. (a) Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187–304. (b) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059–4090. (c) Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489–4505. 3. Concerning NMR studies, see for instance: (a) Bauer, W.; Schleyer, P. V. R. Adv. Carbanion Chem. 1992, 1, 89–175. (b) Gu¨nther, H. J. Braz. Chem. Soc. 1999, 10, 241–262. 4. See for example: (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539–3540. (b) Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452–2458. (c) Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 2001, 123, 4919–4927. (d) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411–14424. 5. ASI Applied Systems, Mettler Toledo. 6. See for example: Leung, W.-P.; Weng, L.-H.; Wang, R.-J.; Mak, T. C. W. Organometallics 1995, 14, 4832–4836. 7. Concerning the formation of complexes between aryllithiums and lithium amides, see: Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. J. Org. Chem. 1998, 63, 8266–8275. 8. Concerning the aggregation of LTMP in solution, see: Wiedemann, S. H.; Ramirez, A.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 15893–15901. 9. (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356–363. (b) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43, 2206–2225. 10. Gros, P.; Choppin, S.; Fort, Y. J. Org. Chem. 2003, 68, 2243–2247. 11. Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg, W. S.; ¨ .; Dykstra, R. R.; Phillips, N. H. J. Am. Gudmundsson, B.O Chem. Soc. 1998, 120, 7201–7210 and references cited. 12. Verbeek, J.; George, A. V. E.; de Jong, R. L. P.; Brandsma, L. J. Chem. Soc., Chem. Commun. 1984, 257–258. 13. Laube, T.; Dunitz, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1373–1393. 14. Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1–360. 15. Bizot, J. Bull. Soc. Chim. Fr. 1967, 151. 16. Kelly, T. R.; Silva, R. A.; Finkenbeiner, G. Tetrahedron Lett. 2000, 41, 9651–9654.