Pd-catalyzed cross-coupling reactions with carbonyls: Application in a very efficient synthesis of 4-aryltetrahydropyridines

Article abstract of DOI:10.1002/chem.200800390

A method is proposed to prepare 4-aryltetrahydropyridines by a Pd-catalyzed cross-coupling reaction by using tosylhydrazone as the nucleophilic coupling agent without stoichiometric organometallic reagent. Palladium-catalyzed couplings can be used for the formation of C-C linkages. It was observed during study that tosylhydrazone can be generated by employing 4-piperidones directly in the cross-coupling reaction with tetrahydropyridines in very high yields. It was also found during study that the ketones and aldehydes can be employed as nucleophilic coupling partners in a reaction without using stoichiometric organometallic reagent. The study concluded that the method can be used to prepare different types of di- and trisubstituted olefins at large scale.

Full text of DOI:10.1002/chem.200800390

DOI: 10.1002/chem.200800390
Pd-Catalyzed Cross-Coupling Reactions with Carbonyls: Application in a
Very Efficient Synthesis of 4-Aryltetrahydropyridines
JosØ Barluenga,* María Tomµs-Gamasa, Patricia Moriel, Fernando Aznar, and
Carlos ValdØs*[a]
Palladium-catalyzed couplings are very powerful tools for
ly useful molecules, and is continuously employed in drug
discovery programs.[12,13–18] 4-Aryltetrahydropyridines have
been synthesized by different approaches starting from com-
mercially available 4-piperidones. In the last few years, Pd-
catalyzed cross-couplings have become the method of
choice (Scheme 1).[14–18] Two different strategies are possible:
[1]
À
the formation of C C linkages. A typical cross-coupling
reaction involves the combination of an electrophile with a
nucleophile in the presence of a metal catalyst. The classical
nucleophilic components are organometallic reagents de-
rived from, for example, magnesium,[2] boron,[3] silicon,[4]
tin,[5] and zinc,[6] whereas the electrophiles are generally or-
ganic halides or sulfonates. Thus, a prerequisite for introduc-
ing an organic fragment by a cross-coupling reaction is its
conversion into either the nucleophilic or the electrophilic
component. In many cases, multistep, expensive, and mois-
ture-sensitive processes are involved in these transforma-
tions.
In the recent years, important advances in the develop-
ment of novel cross-coupling processes that do not require
À
stoichiometric organometallic reagents, such as C H activa-
tion reactions,[7] a-arylations of carbonyl compounds,[8] and
decarboxylative cross-coupling reactions[9] have been dis-
closed.
Scheme 1. Standard methods for the synthesis of 4-aryltetrahydropyri-
dines 2 from 4-piperidones 1 by cross-coupling processes.
In this context, we have recently uncovered a new Pd-cat-
À
alyzed C C bond-forming reaction that employs N-tosylhy-
i) conversion of the ketone into the electrophilic coupling
partner (alkenyl iodide, enol sulfonate), which can be cou-
pled with an organometallic reagent such as boronic acid,[14]
or an stannane,[15] ii) preparation of a vinyl organometallic
reagent from the 4-piperidone,[16] followed by cross-coupling
with an aryl halide.[17–19] Both approaches require several
synthetic steps from the commercially available 4-piperidone
drazones as nucleophilic coupling partner, eliminating the
need of a stoichiometric amount of an organometallic re-
agent.[10] Since then, we have initiated a research program to
evaluate the synthetic potential of this novel reaction. We
identified 4-aryltetrahydropyridines 2 as ideal synthetic tar-
gets for our methodology. The 4-arylpiperidine scaffold is an
important structure for medicinal chemistry,[11] which is pres-
ent in a vast number of biologically active and therapeutical-
À
and proper protection of the piperidone N H group.
In a first run we selected the hydrazone 3a derived from
N-butyloxycarbonylACHTRE(UNG N-Boc)-protected 4-piperidone 1a and
applied the reaction conditions previously reported towards
4-bromotoluene (Scheme 2). A very frustrating result was
obtained. The tetrahydropyridine 4a, which resulted from
the thermal degradation of the tosylhydrazone, was obtained
as the major product, accompanied by only 15% yield of
the desired coupling product 2a (Scheme 2). Several optimi-
zation experiments, with variation of the ligand, base, reac-
tion conditions, and catalyst loading, were performed, but
we were not able to drive the reaction to useful conversions.
[a] Prof. J. Barluenga, M. Tomµs-Gamasa, P. Moriel, Prof. F. Aznar,
Dr. C. ValdØs
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
Juliµn Clavería 8. 33071. Oviedo (Spain)
Fax : (+34)985-103450
E-mail: barluenga@uniovi.es
acvg@uniovi.es
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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Chem. Eur. J. 2008, 14, 4792 – 4795

COMMUNICATION
Table 1. Synthesis of 4-aryltetrahydropyridines 2 from 4-piperidones 1.[a]
Entry
R
t [h]
Compd 2
Yield[b,c]
À
Ar X
1
2
3
4
Et
R’=Me, X=Br
R’=Me, X=Cl
R’=OMe, X=Cl
R’=Cl, X=Br
5
5
6
8
2b
2c
2d
2e
81
93
99
98
Scheme 2. Cross-coupling reaction of the tosylhydrazones 3 with p-bro-
motoluene: Influence of the N-protecting group.
Bn
Bn
Bn
5
6
Bn
Bn
7
2 f
2g
98
97
We then moved to N-alkyl-substituted 4-piperidones. De-
lightfully, when the reaction of the tosylhydrazone 3b (R=
Et) was treated with 4-bromotoluene, in the presence of
12
[Pd2ACHTREUNG(dba)3], XPhos, and LiOtBu in dioxane at 1108C, the
desired coupling product 2b was cleanly obtained in nearly
quantitative yield. This time only traces of the tetrahydro-
pyridine 4b, derived from the decomposition of the tosylhy-
drazone, were detected (Scheme 2). After some experimen-
tation we found that the optimal conditions for this transfor-
mation required 2% mol Pd, a 2:1 ligand/Pd ratio, and 2.3
equivalents of LiOtBu.
7
8
Bn
Bn
7
5
2h
2i
92
92
9
Et
5
6
2j
90
99
10
Bn
2k
Tosylhydrazones 3 are formed by mixing in a solvent to-
sylhydrazine with 4-piperidones 1. Thus, we decided to in-
vestigate whether it might be possible to carry out the cou-
pling reaction starting directly from the piperidone 1 and
the tosylhydrazine, and generating the hydrazone 3 in situ,
in a multicomponent fashion. Indeed, the multicomponent
process provided the coupling product 2b in similar yield to
that obtained from the preformed hydrazone 3b. Products
derived from undesired side reactions, such as ketone a-ary-
lation[8a,b] or tosylhydrazine N-arylation were not observed.
These reaction conditions were applied to an array of aryl
halides (Table 1). We found that the reaction is general for
substituted bromo- and chlorobenzene (Table 1, entries 2, 3,
6) derivatives, bearing electron-donating (Table 1, entries 3,
6) and electron-withdrawing groups (Table 1, entry 5).
Moreover, o-substitution is also tolerated, as seen in the
coupling reaction of bromomesitylene (Table 1, entry 7). As
expected, the reaction with p-chlorobromobenzene gives
rise exclusively the 4-chlorosubstituted derivative (Table 1,
entry 4). The reaction proceeds equally efficiently with aro-
matic heterocycles, both p-exceeding (Table 1, entries 8 and
9) or p-deficient (Table 1, entry 10). Noteworthy, 5-bromoin-
11
Et
5
2l
83
12
13
H
H
19
12
2m
2n
94
90
14[d]
15[d]
16[d]
H
H
H
12
15
24
2o
2p
2q
93
70
76
[a] Experimental conditions: piperidone 1, 1 mmol, TosNHNH2, 1 mmol,
ArX, 1 mmol, [Pd2A(dba)3], 1% mol, Xphos, 4% mol, LiOtBu, 2.3 equiv
dioxane, 1108C. [b] Yield of isolated product. [c] XPhos: 2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl. [d] [Pd2ACHTRE(UNG dba)3], 2% mol and
XPhos, 8% mol.
CTHREUNG
Moreover, the use of dry solvents or an inert atmosphere
is not required for the coupling reaction. The same yields
are obtained when the reactions are carried out in reagent
grade dioxane under air as when the reactions are carried
out in dry solvent under an Ar atmosphere. From a practical
point of view, in this transformation a ketone is employed as
a nucleophilic cross-coupling reagent, with no previous syn-
thetic modification, only the addition of tosylhydrazine to
the reaction medium.
À
dole was successfully coupled without protection of the N
H group (Table 1, entry 11).
À
Interestingly, excellent results were also obtained with N
H unprotected 4-piperidone (Table 1, entries 12–16). The
possible competitive Pd-catalyzed N-arylation was not ob-
served at all. These reactions are slower and in some cases
required an increase in the catalyst loading to achieve com-
plete conversion (Table 1, entries 14-16). Nevertheless, this
is clearly an important advance, since it eliminates the need
for a deprotecting step.
These results prompted us to extend the one-pot process
to other carbonyl compounds. Some preliminary examples
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4793

J. Barluenga, C. ValdØs et al.
Table 2. Synthesis of di- and trisubstituted olefins 6 by direct cross-coupling of carbonyl compounds 5 with
ployed in the cross-coupling re-
action, providing the tetrahy-
dropyridines in very high
yields in most cases. Moreover,
aryl halides.[a,c]
À
N H protection is not re-
quired, thus, enabling further
diversification of the 4-arylpy-
peridines. For all these reasons,
we believe that this reaction
will be of great use in drug dis-
covery programs. Finally, the
one-pot methodology has been
extended to other types of car-
bonyl compounds. Our prelimi-
nary results indicate that a va-
riety of off-the-shelf ketones
and aldehydes can be em-
ployed as nucleophilic coupling
partners in a process, which
does not involve stoichiometric
organometallic reagents, an
inert atmosphere, or dry sol-
vents, and which generates
very few residues. We are con-
vinced that the efficiency of
this transformation, in terms of
yield and availability of the
starting materials, may lead to
it becoming the method of
choice for the preparation of
different types of di- and tri-
substituted olefins, even at
large scale. Investigations on
the scope of this transforma-
À
Entry
1
Carbonyl 5
Ar X
t [h]
Olefin 6
Yield
[%][b]
5
6a
6b
72
96
2
12
3
4
5
12
12
5
6c
6d
6e
98
93
76
6
7
8
9
5
12
6
6 f
6g
6h
6i
92
87
96
60
12
[a] Experimental conditions: Carbonyl 5, 1 mmol, TosNHNH2, 1 mmol, ArX, 1 mmol, [Pd2ACHTRE(UNG dba)3], 1% mol,
XPhos, 4% mol, LiOtBu, 2.3 equiv dioxane, 1108C. [b] Yield of isolated product. [c] XPhos: 2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl.
are presented in Table 2. In all the cases studied, the substi-
tuted olefins 6 are obtained directly from the carbonyl com-
pounds 5 in very high yields. Like in the reaction with 4-pi-
peridones, a-arylation products were never detected. In
terms of scope and stereoselectivity, the results are compara-
ble to those obtained previously for the reaction with pre-
formed tosylhydrazones.[10] For instance, cyclic (Table 2, en-
tries 3, 4) and acyclic (Table 2, entries 1, 2, 5) ketones can
participate in the reaction. Moreover, very good results
were obtained also with aldehydes (Table 2, entries 6–9).
The reactions of 3-phenylpropanal are noteworthy (Table 2,
entries 6, 7). Linear aldehydes are prone to suffer aldol con-
densation; however, in the presence of tosylhydrazine the
only products obtained are the trans olefins 5 derived from
the cross-coupling reaction.
In summary, we have presented an extremely efficient
methodology for the preparation of 4-aryltetrahydropyri-
dines, which are very important building blocks in medicinal
chemistry, by a novel Pd-catalyzed cross-coupling reaction
that employs a tosylhydrazone as the nucleophilic coupling
partner, with no stoichiometric organometallic reagent
added. Importantly, the tosylhydrazone can be generated in
situ, which implies that 4-piperidones can be directly em-
tion are currently underway and will be reported in due
course.
Acknowledgements
Financial support of this work by the DGI of Spain. FPU predoctoral fel-
lowships to M. T.-G. and P. M. are gratefully acknowledged.
Keywords: carbonyl compounds
·
cross-coupling
·
palladium · piperidine · polysubstituted olefins
[1] a) Handbook of Organopalladium Chemistry for Organic Synthesis
(Ed.: E. Negishi), Wiley, Hoboken, NJ, 2002; b) Metal-Catalyzed
Cross-Coupling Reactions (Eds.: A. de Meijere, F. Diederich),
Wiley-VCH, Weinheim, 2004; c) J. Tsuji Palladium Reagents and
Catalysts, Wiley, Chichester, 2004.
[2] a) K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94,
4374; b) R. J. P. Corriu, J. P. Masse, J. Chem. Soc. Chem. Commun.
1972, 144; c) M. Kumada, Pure Appl. Chem. 1980, 52, 669.
[3] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) G. A. Mo-
lander, R. Figueroa, Aldrichimica Acta 2005, 38, 49.
4794
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Pd-Catalyzed Cross-Coupling Reactions with Carbonyls
COMMUNICATION
[4] a) T. Hiyama, Y. Hatanaka, Pure Appl. Chem. 1994, 66, 1471; b) For
a review see: S. E. Denmark, M. H. Ober, Aldrichimica Acta 2003,
36, 75.
[5] J. K. Stille, Angew. Chem. 1986, 98, 504; Angew. Chem. Int. Ed.
Engl. 1986, 25, 508.
[6] a) O. King, N. Okukado, E. Negishi, J. Chem. Soc. Chem. Commun.
1977, 683; b) for a recent review see: E. Negishi, Q. Hu, Z. Huang,
M. Qian, G. Wang, Aldrichimica Acta 2005, 38, 71.
46, 3060; e) S. Sakamuri, I. J. Enyedy, A. P. Kozikowsky, W. A.
Zaman, K. M. Johnson, S. Wang, Bioorg. Med. Chem. Lett. 2001, 11,
495; f) J. C. Barrow, P. G. Nantermet, H. G. Selnick, K. L. Glass,
K. E. Rittle, K. F. Gilbert, T. G. Steele, C. F. Homnick, R. M. Frei-
dinger, R. W. Ransom, P. Kling, D. Reiss, T. P. Broten, T. W. Schorn,
R. S. L. Chang, S. S. OꢁMalley, T. V. Olah, J. D. Ellis, A. Barrish, K.
Kassahun, P. Leppert, D. Nagarathnam, C. Forray, J. Med. Chem.
2000, 43, 2703.
[7] a) For a recent account see: K. Godula, D. Sames, Science 2006, 312,
67. for some relevant recent contributions: b) S. Proch, R. Kempe,
Angew. Chem. 2007, 119, 3196; Angew. Chem. Int. Ed. 2007, 46,
3135; c) K. L. Hull; M. S. Sanford, J. Am. Chem. Soc. 2007, 129,
11904; M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904; d) H.-Q.
Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 12404; e) D. R.
Stuart, K. Fagnou, Science 2007, 316, 1172; f) G. L. Turner, J. A.
Morris, M. F. Greaney, Angew. Chem. 2007, 119, 8142; Angew.
Chem. Int. Ed. 2007, 46, 7996.
[8] Arylation of ketones: a) J. M. Fox, X. Huang, A. Chieffi, S. L. Buch-
wald, J. Am. Chem. Soc. 2000, 122,1360; b) M. Kawatsura, J. F. Hart-
wig, J. Am. Chem. Soc. 1999, 121, 1473; arylation of esters: c) T.
Hama, X. Liu, D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2003,
125, 11176–11177; d) W. A. Moradi, S. L. Buchwald, J. Am. Chem.
Soc. 2001, 123, 7996; arylation of amides: e) T. Hama, D. A. Culkin,
J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 4976; arylation of alde-
hydes: f) Y. Terao, Y. Fukuoka, T. Satoh, M. Miura, M. Nomura,
Tetrahedron Lett. 2002, 43, 101; g) R. M. Martín; S. L. Buchwald,
Angew. Chem. 2007, 119, 7374; Angew. Chem. Int. Ed. 2007, 46,
7236.
[14] a) M. G. Bursavich, C. W. West, D. H. Rich, Org. Lett. 2001, 3, 2317;
b) W. L. Cody, D. D. Holsworth, N. A. Powell, M. Jalaie, E. Zhang,
W. Wang, B. Samas, J. Bryant, R. Ostroski, M. J. Ryan, J. J. Ed-
munds, Bioorg. Med. Chem. 2005, 13, 59.
[15] a) J. Levell, P. Astles, P. Eastwood, J. Cairns, O. Houille, S. Aldous,
G. Merriman, B. Whiteley, J. Pribish, M. Czekaj, G. Liang, S. Mai-
gnan, J.-P. Guilloteau, A. Dupuy, J. Davidson, T. Harrison, A.
Morley, S. Watson, G. Fenton, C. McCarthy, J. Romano, R. Mathew,
D. Engers, M. Gardyan, K. Sides, J. Kwong, J. Tsay, S. Rebello, L.
Shen, J. Wang, Y. Luo, O. Giardino, H.-K. Lim, K. Smith, H. Pauls,
Bioorg. Med. Chem. 2005, 13, 2859; b) J. S. Lee, Y. S. Cho, M. H.
Chang, H. Y. Koh, B. Y. Chungb, A. N. Pae, Bioorg. Med. Chem.
Lett. 2003, 13, 4117.
[16] a) C. A. Quesnelle, P. Gill, S. Roy, M. Dodier, A. Marinier, A.
Martel, L. B. Snyder, S. V. D’Andrea, J. J. Bronson, M. Frosco, D.
Beaulieu, G. A. Warr, K. L. DenBleyker, T. M. Stickle, H. Yang,
S. E. Chaniewski, C. A. Ferraro, D. Taylor, J. W. Russell, K. S. San-
tone, J. Clarke, R. L. Drain, J. O. Knipe, K. Mosure, J. F. Barrett,
Bioorg. Med. Chem. Lett. 2005, 15, 2728; b) A. Darwish, J. M.
Chong, J. Org. Chem. 2007, 72, 1507.
[9] a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662;
b) L. J. Goossen, N. Rodríguez, B. Melzer, C. Linder, G. Deng„
L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824; c) P. Forgione, M.-C.
Brochu, M. St-Onge, K. H. Thesen, M. D. Bailey, F. Bilodeau, J.
Am. Chem. Soc. 2006, 128, 11350; d) O. Baudoin, Angew. Chem.
2007, 119, 1395; Angew. Chem. Int. Ed. 2007, 46, 1373; e) J.-M.
Becht, C. Catala, C. Le Drian, A. Wagner, Org. Lett. 2007, 9, 1781.
[10] J. Barluenga, P. Moriel, C. ValdØs, F. Aznar, Angew. Chem. 2007,
119, 5683.; Angew. Chem. Int. Ed. 2007, 46, 5587.
[11] a) B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Frei-
dinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson,
R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A.
Kunkel, J. P. Springer, J. Hirshfield, J. Med. Chem. 1988, 31, 2235;
b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103,
893.
[17] Suzuki coupling: a) P. L. Eastwood, Tetrahedron Lett. 2000, 41, 3705;
b) G. N. Boice, C. G. Savarin, J. A. Murry, K. Conrad, L. Matty, Edw
G. Corley, H. Smitrovich, D. Hughes, Tetrahedron 2004, 60, 11367;
c) N. Díaz, M. Benvenga, P. Emmerson, R. Favors, M. Mangold, J.
McKinzie, N. Patel, S. Peters, S. Quimby, H. Shannon, M. Siegel, M.
Statnick, E. Thomas, J. Woodland, P. Surface, C. Mitch, Bioorg.
Med. Chem. Lett. 2005, 15, 3844; d) Y. Jiang, C.-A. Chen, K. Lu, I.
Daniewska, J. DeLeon, R. Kong, C. Forray, B. Li, L. G. Hegde, T. D.
Wolinsky, D. A. Craig, J. M. Wetzel, K. Andersen, M. R. Marzabadi,
J. Med. Chem. 2007, 50, 3870.
[18] Stille coupling: a) J. S. Kiely, E. Laborde, L. E. Lesheski, R. A.
Bucsh, J. Heterocycl. Chem. 1991, 28, 1581; b) Q. Tan, E. T. Birzin,
W. Chan, Y. T. Yang, L.-Y. Pai, E. C. Hayes, C. A. DaSilva, F. Di-
Ninno, S. P. Rohrer, J. M. Schaeffer, M. L. Hammond, Bioorg. Med.
Chem. Lett. 2004, 14, 3747; c) D. Kim, L. Wang, J. J. Hale, C. L.
Lynch, R. J. Budhu, M. MacCoss, S. G. Mills, L. Malkowitz, S. L.
Gould, J. A. DeMartino, M. S. Springer, D. Hazuda, M. Miller, J.
Kessler, R. C. Hrin, G. Carver, A. Carella, K. Henry, J. Lineberger,
W. A. Schleif, E. A. Emini, Bioorg. Med. Chem. Lett. 2005, 15, 2129;
d) K. Yoshida, K. Nakayama, N. Kuru, S. Kobayashi, M. Ohtsuka,
M. Takemura, K. Hoshino, H. Kanda, J. Z. Zhang, V. J. Lee, W. J.
Watkins, Bioorg. Med. Chem. 2006, 14, 1993.
[12] A simple Scifinder Scholar search of the 4-arylpiperidine concept
between 1997 and 2007 gave over 50 entries of patents that referred
to the synthesis and/or clinical applications of molecules containing
this moiety.
[13] a) M. V. Patel, T. Kolasa, K. Mortell, M. A. Matulenko, A. A.
Hakeem, J. J. Rohde, S. L. Nelson, M. D. Cowart, M. Nakane, L. N.
Miller, M. E. Uchic, M. A. Terranova, O. F. El-Kouhen, D. L. Don-
nelly-Roberts, M. T. Namovic, P. R. Hollingsworth, R. Chang, B. R.
Martino, J. M. Wetter, K. C. Marsh, R. Martin, J. F. Darbyshire, G.
Gintant, G. C. Hsieh, R. B. Moreland, J. P. Sullivan, J. D. Brioni,
A. O. Stewart, J. Med. Chem. 2006, 49, 7450; b) L. J. Hampson, C.
Arden, L. Agius, M. Ganotidis, M. N. Kosmopoulou, C. Tiraidis, Y.
Elemes, C. Sakarellos, D. D. Leonidas, N. G. Oikonomakos, Bioorg.
Med. Chem. 2006, 14, 7835; c) C. R. Hopkins, M. Czekaj, S. S. Kaye,
Z. Gao, J. Pribish, H. Pauls, G. Liang, K. Sides, D. Cramer, J. Cairns,
Y. Luo, H.-K. Lim, R. Vaz, S. Rebello, S. Maignan, A. Dupuy, M.
Mathieue, J. Levell, Bioorg. Med. Chem. Lett. 2005, 15, 2734;
d) S. A. Filla, B. M. Mathes, K. W. Johnson, L. A. Phebus, M. L.
Cohen, D. L. Nelson, J. M. Zgombick, J. A. Erickson, K. W. Schenck,
D. B. Wainscott, T. A. Branchek, J. M. Schaus, J. Med. Chem. 2003,
[19] C. Morrill, N. S. Mani, Org. Lett. 2007, 9, 1505.
[20] We speculate that the dramatically different behavior between N-
Boc and N-alkyl tosylhydrazones, might be due to the particular
steric requirements imposed by the Boc group. According to our
mechanistic proposal (see ref. [10]), the last step of the catalytic
cycle is a b-hydrogen elimination, requiring a syn arrangement of
the Pd and the hydrogen atom, which might be difficult in the N-
Boc-substituted system. Therefore, the thermal uncatalyzed tosylhy-
drazone decomposition to give tetrahydropyridine 3 becomes the
main reaction pathway.
Received: March 4, 2008
Published online: April 15, 2008
Chem. Eur. J. 2008, 14, 4792 – 4795
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4795