Selective and multiple functionalization of pyridines and alkaloids via Mg- and Zn-organometallic intermediates

Article abstract of DOI:10.1021/ol200563j

Chemical equations presented. Quinine, nicotine, and related electron-rich amino-substituted pyridines were readily metalated using LiCl-solubilized TMP (2,2,6,6-tetramethylpiperidyl) bases in the presence of BF₃· OEt₂. A full pyridi

Full text of DOI:10.1021/ol200563j

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2306–2309
Selective and Multiple Functionalization of
Pyridines and Alkaloids via Mg- and Zn-
Organometallic Intermediates
Milica Jaric, Benjamin A. Haag, Sophia M. Manolikakes, and Paul Knochel*
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13,
€
81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received March 2, 2011
ABSTRACT
Quinine, nicotine, and related electron-rich amino-substituted pyridines were readily metalated using LiCl-solubilized TMP (2,2,6,6-
tetramethylpiperidyl) bases in the presence of BF3 OEt2. A full pyridine functionalization of all five positions of the pyridine ring can be
3
realized by using an appropriate combination of TMP bases in the presence or absence of BF3 OEt2.
3
The functionalization of pyridines is an active research
field triggered by the diverse biological activities of this
class of heterocycles.1 The preparation of polyfunctional
pyridines can be achieved by ring metalation,2 CÀH
activation,3 or radical functionalization.4 Recently, we
have found that the combination of the hindered base
TMPMgCl LiCl5 (1) with BF3 OEt2 allows the regiose-
lective metalation of various electron-poor pyridines.6 The
metalation of electron-rich substituted pyridines, bearing
amino groups, or in general the metalation of alkaloids is
of great importance due to their pharmaceutical properties.7
3
3
(1) (a) Henry, G. D. Tetrahedron 2004, 29, 6043. (b) Marazano, C. In
Six-Membered Hetarenes with One Nitrogen or Phosphorus Atom; Black,
D. S. C., Ed.; Science of Synthesis; Georg Thieme: Stuttgart, 2005; Vol. 1.
(c) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 1161. (d)
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Zhdankin, V. V., Eds. Comprehensive Heterocyclic Chemistry III;
Elsevier: Oxford, 2008; Vols. 7À9. (e) Hill, M. D. Chem.;Eur. J. 2010,
16, 12052.
The use of BF3 OEt2 for the activation of such basic
3
substrates may be complicated by competitive BF3 com-
plexation to the amino substituents.8 Herein, we report the
selective metalation of various amino-substituted pyri-
dines, including important alkaloids such as nicotine and
quinine. Also, we report successive metalation of the
pyridine scaffold, allowing a full ring functionalization.
Thus, the reaction of 4-dimethylaminopyridine (2a;
(2) (a) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29,
773. (b) Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Mongin, F.;
ꢀ
ꢀ
Queguiner, G. Tetrahedron 2001, 57, 4059. (d) Turck, A.; Ple, N.;
ꢀ
Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489. (e) Karig, G.;
Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3, 835. (f) Schlosser, M.
Angew. Chem., Int. Ed. 2005, 44, 376. (g) Mulvey, R. E.; Mongin, F.;
Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802. (h)
Gros, P. C.; Fort, Y. Eur. J. Org. Chem. 2009, 4199. (i) Khartabil, H. K.;
DMAP)9 with BF3 OEt2 (1.1 equiv, THF, 0 °C, 15 min)
ꢀ
Gros, P. C.; Fort, Y.; Ruiz-Lopez, M. F. J. Am. Chem. Soc. 2010, 132,
3
2410.
(3) (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (b) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (c) Li, B.; Wu, Z.-H.; Gu, Y.-F.; Sun, C.ÀL.;
Wang, B.-Q.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 1109. (d)
(5) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
(6) Jaric, M.; Haag, B. A.; Unsinn, A.; Karaghiosoff, K.; Knochel, P.
Angew. Chem., Int. Ed. 2010, 49, 5451.
ꢀ
Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Herrebout,
W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J.
2010, 16, 13063.
(7) (a) Verpoorte, R.; Schripsema, J.; van der Leer, T. Alkaloids 1988,
34, 331. (b) Gros, P. C.; Doudouh, A.; Woltermann, C. Org. Biomol.
Chem. 2006, 4, 4331. (c) Cordell, G. A. The Alkaloids: Chemistry and
Biology; Academic Press: Oxford, 2010; Vol. 69.
(8) (a) Kessar, S. V.; Singh, P.; Singh, A. K.; Kaul, V. K. Indian J.
Chem. 1994, 33B, 818. (b) Kessar, S. V.; Vohra, R.; Kaur, N. P.; Singh,
K. N.; Singh, P. J. Chem. Soc., Chem. Commun. 1994, 1327. (c) Kessar,
S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
(4) (a) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem.
1990, 27, 79. (b) Harrowven, D. C.; Sutton, B. J. Prog. Heterocycl. Chem.
2004, 16, 27. (c) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
13194. (d) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Wiley-Black-
well: Chichester, 2010; Vol. 5.
r
10.1021/ol200563j
Published on Web 04/04/2011
2011 American Chemical Society

TMPMgCl LiCl (1; 1.5 equiv, 0 °C, 2.5 h) leads to a
selective metalation at position 6. After transmetalation
3
Scheme 1. Selective Functionalization of 2a and 2b Using a
Two-Step Metalation Protocol
with CuCN 2LiCl (1.1 equiv) and addition of 3-bromo-
cyclohexene (0.8 equiv), the allylated nicotine derivative
(4b) is obtained in 92% yield (Scheme 1).
3
Table 1. Selective Metalation of Amino-Substituted N-
Heterocycles
followed by the addition of TMPMgCl LiCl (1; 1.1 equiv,
3
0 °C, 1 h) furnishes the 2-pyridyltrifluoroborate10 inter-
mediate 3a, which after transmetalation with ZnCl211 and
Pd(0)-catalyzed cross-coupling12 using Pd(dba)2 and P(2-
furyl)313 with 4-iodoanisole, leads to the 2-arylated DMAP
(4a) in 81% yield (Scheme 1). In the absence of BF3 OEt2,
3
the metalation of 2a with TMPMgCl LiCl (1) leads mostly
3
to decomposition. Similarly, the reaction of the trifluor-
oborate 3a with other electrophiles such as iodine, 1,1,2-
trichloro-1,2,2-trifluoroethane, and an acyl chloride (after
CuCN 2LiCl14transmetalation) gives the expected prod-
3
ucts (4cÀe) in 68À72% yield (entries 1À3 of Table 1).
The 2-chloro-DMAP derivative (4d) can be further meta-
lated atposition 6 usingthe same conditions ((i) BF3 OEt2,
3
0 °C; (ii) TMPMgCl LiCl (1; 1.5 equiv, 0 °C, 3 h)) and
3
provides after iodolysis or copper-mediated allylation the
2,6-functionalized DMAP derivatives (4gÀh) in 78À80%
yield (entries 5 and 6). A sterically hindered 4-aminopyr-
idine derivative such as 2c bearing a tetramethylpiperidyl
moiety at position 4 is metalated under the same condi-
tions. Allylation with ethyl 2-(bromomethyl)acrylate15
gives the 2-allylated pyridine (4f) in 71% yield. Whereas
nicotine was previously metalated with various lithium
amide16,17 or TMP-zincate16 bases in a nonselective man-
ner, we have found that (S)-nicotine (2b) can be selectively
metalated under mild conditions using our procedure.
a Isolated, analytically pure product. b Obtained after transmetala-
tion with CuCN 2LiCl (1.1 equiv).
3
The functionalization of quinine18 was pioneered by
Hintermann, Gaunt, Ley, and Baran using either radical
ornucleophilicadditions.4c,19 Ourmetalation protocol was
readily applied to this more complex scaffold and allows
for the first time to metalate at either position 2 or 3 of the
quinoline ring selectively. Thus, the successive treatment of
quinine (5) with MeLi (1 equiv, 0 to 25 °C, 1 h) and
Thus, the treatment of (S)-nicotine (2b) with BF3 OEt2
(1.1 equiv, 0 °C, 15 min) followed by the addition of
3
BF3 OEt2 (2.2 equiv, 0 °C, 15 min) in THF followed by
3
€
€
(9) (a) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int.
Ed. 1978, 17, 569. (b) For a metalation of DMAP with a potassium
zincate, see: Conway, B.; Graham, D. V.; Hevia, E.; Kennedy, A. R.;
Klett, J.; Mulvey, R. E. Chem. Commun. 2008, 2638.
(10) The nature of the intermediate organometallic produced after
metalation has been established by 13C and 11B NMR spectroscopy
(ref 6).
the addition of TMPMgCl LiCl (1; 1.1 equiv, 0 °C, 40min)
3
leads to a specific metalation at position 3 of the quinoline
ring triggered by a chelation with the tertiary amine.
Quenching with various electrophiles, such as iodine, 1,2-
dibromo-1,1,2,2-tetrachloroethane, allyl bromide, and
ethyl 4-iodobenzoate in the presence of the appropriate
catalyst, produces the 3-substituted quinine derivatives
(11) Without a transmetalation with ZnCl2, the cross-coupling pro-
ceeds in lower yields.
(12) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240.
(13) Farina, V.; Baker, S. R.; Benigni, D. A.; Sapino, C. Tetrahedron
Lett. 1988, 29, 5739.
(18) (a) Hoffmann, H. M. R.; Frackenpohl, J. Eur. J. Org. Chem.
ꢀ
2004, 4293. (b) Kaufman, T. S.; Ruveda, E. A. Angew. Chem., Int. Ed.
(14) (a) Knochel, P.; Yeh, M.; Berk, S.; Talbert, J. J. Org. Chem.
1988, 53, 2390. (b) Knochel, P.; Rao, S. A. J. Am. Chem. Soc. 1990, 112,
6146.
2005, 44, 854. (c) Seeman, J. I. Angew. Chem., Int. Ed. 2007, 46, 1378.
(19) (a) Laurie, W. A.; Mc Hale, D.; Saag, K. Tetrahedron 1986, 42,
3711. (b) Coors, C.; Matusch, R. Arch. Pharm. 1989, 322, 817. (c)
Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith,
S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024. (d)
Hintermann, L.; Schmitz, M.; Englert, U. Angew. Chem., Int. Ed.
2007, 46, 5164.
ꢀ
(15) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
ꢀ
(16) Fevrier, F. C.; Smith, E. D.; Comins, D. L. Org. Lett. 2005, 7,
5457.
(17) Wagner, F. F.; Comins, D. L. Eur. J. Org. Chem. 2006, 3562.
Org. Lett., Vol. 13, No. 9, 2011
2307

(6aÀd) in 40À66% yield (Scheme 2). By increasing the
steric bulk near the quinuclidine nitrogen via the formation
of TBDMS-ether 7 (97% yield),20 it was possible to shift
the metalation from position 3 to position 2 of the quino-
line ring. Thus, the two-step metalation of 7, with
Scheme 3. Full functionalization of the Pyridine Core Starting
from the 2,5-Dihalopyridine (9)
BF3 OEt2/TMPMgCl LiCl (1, 1.5 equiv, 0 °C, 15 h),
3
3
produces, after quenching with iodine or copper-catalyzed
allylation, the 2-substituted quinines 8a and 8b in 41À44%
yield (Scheme 2).
Scheme 2. Functionalization of Quinine (5) either at C3 or at C2
Position
The full functionalization of a 4-substituted pyridine
such as 10 proceeds best by a BF3 OEt2-assisted zincation
3
using TMP2Zn 2MgCl2 2LiCl (14; 0.55 equiv, À20 °C, 3
3
3
h) leading after bromination (Br2, 1.1 equiv, À20 to 25 °C)
to the 3,4-disubstituted pyridine 17. The regioselectivity of
the metalation may be explained by assuming that BF3
coordinates at the N-heterocycle and disfavors for steric
reasons a metalation at position 2, but the BF3 activation
acidifies all positions and allows a fast metalation at
position 3. Also the cyano group directs by its inductive
effect the metalation in position 3 or 4. Further magnesia-
tion of 17 with TMPMgCl LiCl (1, 1.1 equiv, À78 °C, 1 h)
3
and a copper-catalyzed allylation with 3-bromocyclohex-
ene give the 2,3,4-trisubstituted pyridine 18 in 65% yield.
Repeated magnesiation with TMPMgCl LiCl (1; 1.1
3
equiv, À30 °C, 4 h) readily generates the Grignard reagent
19, which after iodolysis provides the tetrasubstituted
pyridine 20 in 67% yield. The final functionalization is
achieved by treatment of 20 with the mild zinc base
TMP2Zn 2MgCl2 2LiCl21 (14; 1.1 equiv, 25 °C, 20 h)
To demonstrate further the broad range of applications
of this pyridine metalation with an appropriate choice of
TMP-bases in the presence (or absence) of BF3 OEt2, we
have performed two full functionalization sequences of the
pyridine scaffold starting first with the 2,5-dihalopyridine
9 and with isonicotinonitrile (10) (Schemes 3 and 4). Thus,
3
3
3
giving after a copper-catalyzed allylation the fully substi-
tuted pyridine 21 in 62% yield (Scheme 4).
pyridine 9 was first treated with TMPMgCl LiCl (1, 1.1
equiv, À40 °C, 3 h) leading to a regiospecific metalation at
3
Scheme 4. Full Functionalization of the Pyridine Core Starting
from the 4-Substituted Pyridine (10)
position 6.
Quenching with tosyl cyanide results in the formation of
the 2,3,6-trisubstituted pyridine 11 in 68% yield. Subse-
quent metalation with 1 (1.1 equiv, À78 °C, 10 min)
achieves a further magnesiation at position 4, leading to
the functionalized Grignard reagent 12. Its thiomethyla-
tion with MeSO2SMe provides the 2,3,4,6-tetrasubstituted
pyridine 13 in 81% yield. Whereas TMPMgCl LiCl (1)
is incompatible with such sensitive pyridines, TMP2
3
Zn 2MgCl2 2LiCl21 (14) smoothly zincates the pyridine
3
3
13 at position 5, leading to the bis-pyridylzinc reagent 15.
The copper-mediated acylation with PhCOCl leads to the
fully substituted pyridine 16 in 61% yield (Scheme 3).
(20) Besenius, P.; Cormack, P. A. G.; Liu, J.; Otto, S.; Sanders,
J. K. M.; Sherrington, D. C. Chem.;Eur. J. 2008, 14, 9006.
(21) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007,
46, 7685. (b) Dong, Z.; Clososki, G. C.; Wunderlich, S. H.; Unsinn, A.;
Li, J.; Knochel, P. Chem.;Eur. J. 2009, 15, 457.
In summary, we have demonstrated that TMP bases in
the presence of BF3 OEt2 are versatile reagents for the
3
2308
Org. Lett., Vol. 13, No. 9, 2011

functionalization of amino-substituted pyridines and al-
kaloids. Furthermore, the functionalization of quinine (5)
at position 2 or 3 was demonstrated as well as the possi-
bility of fully functionalizing pyridines via successive me-
talations using TMP bases in the presence or absence of
Framework Programme (FP7/2007-2013) ERC Grant
Agreement No. 227763 and the Deutsche Forschungsge-
meinschaft (DFG) for financial support. We also thank
BASF AG (Ludwigshafen), W. C. Heraeus (Hanau), and
Chemetall GmbH (Frankfurt) for the generous gift of
chemicals.
BF3 OEt2. Further extensions of this work toward the
synthesis of functionalized alkaloids are underway in our
laboratories.
3
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank the European Research
Council under the European Community’s Seventh
Org. Lett., Vol. 13, No. 9, 2011
2309