Divergent Pd-catalyzed and radical cyclizations of nucleophilic cyclic enamines derived from functionalized amine and aldehyde fragments

Article abstract of DOI:10.1021/jo800619m

(Chemical Equation Presented) Tetrahydropyridines carrying pendant halide functionality at the enamine β-carbon have been prepared by condensation between appropriately functionalized aldehydes and a vinylogous Mannich adduct. Those enamines display divergent behavior in radical and Heck reactions. Thus, radical addition takes place in a 5-exo-trig fashion whereas Heck couplings follow a 6-endo-trig pathway. The resulting polycyclic products are obtained with high regio- and stereoselectivity.

Full text of DOI:10.1021/jo800619m

SCHEME 1. Formation of Tetrahydropyridines from
Amines and Aldehydes
Divergent Pd-Catalyzed and Radical Cyclizations
of Nucleophilic Cyclic Enamines Derived from
Functionalized Amine and Aldehyde Fragments
Jose´ M. Aurrecoechea,* Carlos A. Coy,† and
Oscar J. Patin˜o†
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia
y Tecnolog´ıa, UniVersidad del Pa´ıs Vasco, Apartado 644,
48080 Bilbao, Spain
SCHEME 2. Strategy to Polycyclic Building Blocks 7 and 8
jm.aurrecoechea@ehu.es
ReceiVed March 18, 2008
Tetrahydropyridines carrying pendant halide functionality at
the enamine ꢀ-carbon have been prepared by condensation
between appropriately functionalized aldehydes and a viny-
logous Mannich adduct. Those enamines display divergent
behavior in radical and Heck reactions. Thus, radical addition
takes place in a 5-exo-trig fashion whereas Heck couplings
follow a 6-endo-trig pathway. The resulting polycyclic
products are obtained with high regio- and stereoselectivity.
to the enamine double bond through intermediates 5 and 6,
respectively (Scheme 2). Compounds with general structures 7
and 8 are interesting as functionalized building blocks because
their respective azaspirocyclic and tricyclic benzo[h]quinoline
basic skeletons are found in a number of biologically active
products.4 A condensation/cyclization approach to these com-
pounds (Schemes 1 and 2) would be attractive because of its
simplicity, conciseness, and flexibility to introduce precursors
for various types of C-radicals and Pd-complexes through simple
aldehydes 2. Furthermore, because R, R1, and R3 are necessarily
alkyl groups in 3 and 4, these cyclizations would involve
nucleophilic cyclic enamine intermediates of the general types
represented by 9 and 10, which have seldom been reported
except for indole-type enamines.5,6 Moreover, in the case of
radicals 9, the cyclizations are poorly regioselective5b unless
additional activation is provided at the enamine R-position.5a
The condensation between vinylogous Mannich adducts 1 and
aldehydes 2 leads to cyclic enamines 3 (Scheme 1), and this
reaction has found recent use in the preparation of polysubsti-
tuted piperidine derivatives via hydrogenation reactions as well
as nucleophilic addition- and reductive-type couplings.1
Appropriately substituted tetrahydropyridines 4 could in
principle be envisaged as precursors of polycyclic systems 7
and/or 8 via intramolecular radical-2 or Heck-type3 additions
(4) See: (a) Khan, F. A.; Dash, J. J. Org. Chem. 2003, 68, 4556–4559. (b)
McManus, A. H.; Fleming, M. J.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46,
433–436. (c) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9,
367–370, and references cited therein.
† Present address: Departamento de Qu´ımica, Facultad de Ciencias, Univer-
sidad Nacional de Colombia, Bogota´ D.C., Colombia.
(1) (a) Aurrecoechea, J. M.; Gorgojo, J. M.; Saornil, C. J. Org. Chem. 2005,
70, 9640–9643. (b) Aurrecoechea, J. M.; Suero, R.; de Torres, E. J. Org. Chem.
2006, 71, 8767–8778.
(5) Radical reactions of type 9 with indole derivatives: (a) Yang, C. C.; Chang,
H. T.; Fang, J. M. J. Org. Chem. 1993, 58, 3100-3105. (b) Flanagan, S. R.;
Harrowven, D. C.; Bradley, M. Tetrahedron Lett. 2003, 44, 1795-1798 and
references cited therein. For reactions involving N-sulfonyl- or N-methoxycar-
bonyl enamines, see:(c) Ahman, J.; Somfai, P. J. Chem. Soc., Perkin Trans. 1
1994, 1079–82. (d) Parsons, P. J.; Penkett, C. S.; Cramp, M. C.; West, R. I.;
Warrington, J.; Saraiva, M. C. Synlett 1995, Sp. Iss., 507–509. (e) Parsons, P. J.;
Penkett, C. S.; Cramp, M. C.; West, R. I.; Warren, E. S. Tetrahedron 1996, 52,
647–60.
(2) Reviews: (a) Parsons, A. F. C. R. Acad. Sci., Ser. II 2001, 4, 391–400.
(b) Clark, A. J. Chem. Soc. ReV. 2002, 31, 1–12. (c) Bowman, W. R.; Fletcher,
A. J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans 1 2002, 2747–2762. (d)
Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695–713. (e) Majumdar, K. C.;
Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron 2005, 61, 10603–10642.
(3) Reviews: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100,
3009–3066. (b) Larhed, M.; Hallberg, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E. Ed.; Wiley and Sons: New York,
2002; Vol. 1, pp 1133-1178. (c) Braese, S.; de Meijere, A. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F. Eds.; Wiley-
VCH: Weinheim, Germany, 2004; Vol. 1, pp 217-315.
(6) Heck reaction of type 10 with indole derivatives: (a) Joucla, L.; Putey,
A.; Joseph, B. Tetrahedron Lett. 2005, 46, 8177–8179. (b) Avila-Zarraga, J. G.;
Lujan-Montelongo, A.; Covarrubias-Zuniga, A.; Romero-Ortega, M. Tetrahedron
Lett. 2006, 47, 7987–7989.
5194 J. Org. Chem. 2008, 73, 5194–5197
10.1021/jo800619m CCC: $40.75 2008 American Chemical Society
Published on Web 06/05/2008

TABLE 1. Preparation of Tetrahydropyridines 12
TABLE 2. Radical Cyclizations of Enamines 12
Therefore, the possibility of using tetrahydropyridines of type
4 appeared to be worth exploring since this would provide an
opportunity to further examine the radical and Pd-catalyzed
chemistry of the enamine functional group. In this paper we
report an expeditious and divergent approach to building blocks
of general types 7 and 8 through a common tetrahydropyridine
4 utilizing highly regio- and stereoselective 5-exo-trig radical
additions and 6-endo-trig Heck couplings, respectively.7
Amine 111b,8 and aldehydes 2a-d were selected as precursors
of representative substrates for radical and Pd-catalyzed reac-
tions. The choice of amine 11 as a convenient starting material
was dictated by its ready availability in multigram quantities.1b
Aldehydes 2a-c were known compounds,9 while the prepara-
tion of 2d followed the procedure reported for 2c.9c Tetrahy-
dropyridines 12a-d were then prepared by condensation
between 11 and 2a-d in CH2Cl2 at room temperature with the
yields indicated in Table 1. Enamines 12 were conveniently
purified by column chromatography and could be stored for
several days without appreciable degradation, with the exception
of 12a, which underwent self-decomposition on standing at room
temperature and had to be used soon after purification. This is
not completely surprising since 12a holds at the same time a
nucleophilic enamine and an alkylating agent. In any case, it is
remarkable that reaction conditions are mild enough to allow
the preparation of this type of compound.
a Ratio of 13 to an undetermined mixture of isomers.
°C resulted in the formation of spirocycles 13 in good yields
(Table 2). Products derived from alkyl (entry 1), vinyl (entry
2), or aryl (entries 3 and 4) radicals are all effectively obtained
in a highly regio- and stereoselective fashion, with the alternative
regioisomers 14 and/or stereoisomers being formed in only
minor amounts. In the reaction of 12b a furoquinoline derivative
of type 14 was clearly identified by comparison of diagnostic
13C NMR signals with those of the spiro derivative 13b. Thus,
a CH2 unit and the characteristic spirocyclic quaternary carbon
of 13b were replaced by two CH carbons in the corresponding
regioisomer. As expected, the major stereoisomer in these
reactions was formed by radical addition to the less congested
face of the enamine double bond, i.e., anti to the fused lactone
moiety. This was determined for 13b-d by the observation of
NOE’s between the lactone bridgehead protons and either one
vinylic hydrogen (in the case of 13b) or the aromatic o-H
proximal to the spirocyclic quaternary carbon (in the case of
13c and 13d).
The cyclizations depicted in Table 2 represent an unusual
type involving the addition of a nucleophilic C-radical to an
electron-rich enamine double bond. This polarity mismatch has
been shown to retard the rate of addition of nucleophilic
C-radicals to enamines,10 and as a result, intermolecular
reactions have mainly employed electrophilic radicals containing
Treatment of tetrahydropyridines 12 under typical radical
cyclization conditions with (TMS)3SiH/AIBN in toluene at 100
(7) Related 6-endo-trig radical and 6-exo-trig Pd-catalyzed reactions have
been reported for enamide-type systems with the cyclizing chain attached to the
enamide R-carbon. Radical: (a) Ripa, L.; Hallberg, A. J. Org. Chem. 1998, 63,
84–91. Pd-catalyzed: (b) Ripa, L.; Hallberg, A. J. Org. Chem. 1996, 61, 7147–
7155. (c) Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595–602. (d) Lindstrom,
S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291–2293.
(10) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753–764.
(11) (a) Renaud, P.; Schubert, S. Angew. Chem., Int. Ed. Engl. 1990, 29,
433–434. (b) Renaud, P.; Schubert, S. Synlett 1990, 624–626. (c) Russell, G. A.;
Wang, K. J. Org. Chem. 1991, 56, 3475–3479. (d) Curran, D. P.; Thoma, G.
J. Am. Chem. Soc. 1992, 114, 4436–4437. (e) Renaud, P.; Bjo¨rup, P.; Carrupt,
P. A.; Schenk, K.; Schubert, S. Synlett 1992, 211–213. (f) Schubert, S.; Renaud,
P.; Carrupt, P. A.; Schenk, K. HelV. Chim. Acta 1993, 76, 2473–2489. (g) Chuang,
C.-P.; Wu, Y.-L. Tetrahedron 2004, 60, 1841–1847. (h) Tsai, A.-I.; Chuang,
C.-P. Tetrahedron 2006, 62, 2235–2239.
(8) Ha, H.-J.; Kang, K.-H.; Ahn, Y.-G.; Oh, S.-J. Heterocycles 1997, 45,
277–286.
(9) (a) Hon, Y. S.; Chang, F. J.; Lu, L.; Lin, W. C. Tetrahedron 1998, 54,
5233–5246. (b) Brebion, F.; Vitale, M.; Fensterbank, L.; Malacria, M. Tetra-
hedron: Asymmetry 2003, 14, 2889–2896. (c) Gibson, S. E.; Jones, J. O.;
McCague, R.; Tozer, M. J.; Whitcombe, N. J. Synlett 1999, Sp. Iss., 954–956.
J. Org. Chem. Vol. 73, No. 13, 2008 5195

electron-withdrawing groups,11 while the corresponding in-
tramolecular reactions5,12 have been mostly limited to indole
derivatives5,12e and to enamines with additional activation
provided by aryl groups.12b–d Alternatively, the less nucleophilic,
as well as more stable and easier to handle, enamide-type
systems have been widely employed in a variety of synthetic
applications.2 In fact, the reactions reported here appear to be
the first examples of 5-exo-trig radical cyclizations of systems
of type 9 (R ) alkyl) not involving indole derivatives.
SCHEME 3. Heck Reactions of Tetrahydropyridines 12
The regiochemistry of these radical cyclizations follows the
trends observed with typical hex-5-enyl radicals, which are
known to cyclize with high 5-exo-trig selectivity.13,14 In addition,
in this particular case, the observed 5-exo-trig mode of addition
is also consistent with the tendency displayed by intermolecular
radical additions to unconstrained enamines, where the regio-
chemistry appears to be governed by the preservation of
conjugation. As a result, addition takes place at the enamine
ꢀ-carbon with formation of a relatively stable R-aminoalkyl
radical.11 However, 5-exo to 6-endo cyclization ratios have also
been found to be very dependent on the extent of steric
congestion around the alkene terminus. For example, for simple
model systems, the ratio 5-exo/6-endo goes from nearly 50:1
in the unsubstituted hex-5-enyl radical to approximately 1:2 in
the 5-methylhex-5-enyl case.13,14 Therefore, in the cyclizations
of sterically encumbered enamines 12 the driving force provided
by the formation of an R-aminoradical 15 is remarkable,
particularly in the more substituted cases of 12b-d.
in the reaction of electron-rich-substituted phenyl derivative 12d,
and this could also be related to the use of that halide-scavenger
additive.17 Thus, in the presence of Tl(I) a cationic pathway is
presumably involved17 and, in that case, addition of the electron-
rich aryl group to the more electron-deficient R-carbon is
expected to be particularly favorable.18 Formation of both 16
and 17 took place with very high stereoselectivity since no other
stereoisomers were found. The stereochemistry of 16 and 17
was unambiguously established by NOE experiments and is
consistent with a reaction course involving carbopalladation
from the less hindered face of the enamine double bond,
followed by ꢀ-H elimination with the exocyclic methylene unit.
In conclusion, starting from readily available aldehydes 2 and
amine 11, the tactical combination of a condensation step and
either a radical- or Heck-type ring-closure provides a rapid build-
up of molecular complexity in a regiodivergent and very
stereoselective manner. The different regiochemistries displayed
by the radical and Pd-catalyzed reactions make the two methods
complementary, a feature also recognized in earlier work.7
Additionally, the presence of a lactone ring in 13 and 16 is
particularly convenient as it offers further possibilities for
structural diversification.1b It is noted, however, that simpler
tetrahydropyridines 3 (EWG ) CO2Et) are similarly available
from acyclic R,ꢀ-unsaturated esters.1a All of these combined
features contribute to make the methodology appealing for the
preparation of structurally diverse families of polycylic nitrogen
heterocycles.
The reactivity of enamines 12c,d under typical Heck condi-
tions was examined next. Ample precedent existed on the use
of enamides, formamidines, enaminones, enaminoesters, dehy-
droaminoesters, pyrroles, and indoles, which have all been
extensively utilized in intramolecular Heck reactions.3,6,15
However, reports on the alternative use of simple enamines are
very scarce and, in any case, restricted to 5-endo additions at
the enamine ꢀ-position.15c,16 After some experimentation, condi-
tions which led efficiently to intramolecular arylation products
were found (Scheme 3). The major products 16 displayed an
alkene moiety exocyclic to the piperidine ring, and were
accompanied by minor amounts of double bond isomerization
products 17. The use of TlOAc as additive was found to be
important to minimize this isomerization,7b,c,17 as shown by the
increased amount of 17c (16c/17c ) 1.4:1, 52%) obtained when
TlOAc was replaced by KOAc under otherwise similar condi-
tions. Additionally, a significantly higher efficiency was noticed
Experimental Section
General Procedure for the Preparation of Tetrahydropy-
ridines 12. In a typical experiment, to a solution of amine 111b,8
(0.402 g, 1.98 mmol) and the appropriate aldehyde 2 in CH2Cl2
(24 mL) was added powdered 4 Å molecular sieves (4.0 g), and
the resulting suspension was stirred at room temperature for 14 h.
The mixture was filtered over Celite and the solid was washed with
CH2Cl2 (3 × 15 mL). Evaporation of the combined filtrates afforded
an oil that was purified by flash chromatography (silica gel saturated
with Et3N) under the conditions indicated in the Supporting
Information for the individual cases.
General Procedure for Radical Cyclizations of Tetrahydropy-
ridines 12: Preparation of Azaspirocycles 13. In a typical experi-
ment, a solution of 12 (1.0 mmol), AIBN (0.164 g, 0.30 mmol),
and (TMS)3SiH (616 µL, 2.0 mmol) in toluene (10 mL) was heated
at 100 °C (oil bath temperature) for 16 h under Ar. After cooling,
the mixture was either diluted with EtOAc (15 mL) and extracted
with 1 M HCl (4 × 20 mL) (in the case of 12a and 12b) or,
alternatively, evaporated to dryness, then the resulting residue was
redissolved in EtOAc (20 mL) and extracted with 1 M HCl (3 ×
15 mL) (in the case of 12c and 12d). In either case, the acidic
extracts were basified with saturated NaHCO3 to pH 8, the solution
was extracted with CH2Cl2 (3 × 25 mL), and the organic extracts
were washed with brine (10 mL) and dried (Na2SO4). The residue
after evaporation was purified by flash chromatography (silica gel
saturated with Et3N) under the conditions indicated in the Sup-
porting Information for the individual cases.
(12) (a) Glover, S. A.; Warkentin, J. J. Org. Chem. 1993, 58, 2115–2121.
(b) Cladingboel, D. E.; Parson, P. J. J. Chem. Soc., Chem. Commun. 1990, 1543–
1544. (c) Ozlu, Y.; Cladingboel, D. E.; Parsons, P. J. Synlett 1993, 357–358. (d)
Oezlue, Y.; Cladingboel, D. E.; Parsons, P. J. Tetrahedron 1994, 50, 2183–
2206. (e) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K. Tetrahedron 2004,
60, 3273–3282.
(13) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925–3941.
(14) Beckwith, A. L. J. Chem. Soc. ReV. 1993, 22, 143–151.
(15) Recent examples: (a) Sorensen, U. S.; Pombo-Villar, E. HelV. Chim.
Acta 2004, 87, 82–89. (b) Wu, X.; Nilsson, P.; Larhed, M. J. Org. Chem. 2005,
70, 346–349. (c) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571–
2577. (d) Michael, J. P.; de Koning, C. B.; Mudzunga, T. T.; Petersen, R. L.
Synlett 2006, 3284–3288.
(16) Ackermann, L.; Althammer, A. Synlett 2006, 3125–3129.
(17) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
5196 J. Org. Chem. Vol. 73, No. 13, 2008

General Procedure for Heck Cyclizations of Tetrahydropy-
ridines 12: Preparation of Tetracycles 16 and 17. In a typical
experiment, a solution of 12 (0.50 mmol), Pd(OAc)2 (5.61 mg, 0.025
mmol), o-tolylphosphine (0.015 g, 0.050 mmol), and thalium acetate
(0.145 g, 0.55 mmol) in DMF (6.0 mL) was stirred at 120 °C (oil
bath temperature) for 3.5-6 h under Ar. After cooling, the solvent
was evaporated and the remaining solid was purified by flash
chromatography (silica gel saturated with Et3N) under the conditions
indicated in the Supporting Information for the individual cases.
Supporting Information Available: Characterization data,
stereochemical elucidation details, and copies of 1H NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800619M
(18) (a) Vallin, K. S. A.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg, A.
J. Org. Chem. 2003, 68, 6639–6645. (b) Andappan, M. M. S.; Nilsson, P.; Von
Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212–5218. (c) Mo, J.; Xu,
L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751–760. (d) Mo, J.; Liu, S.; Xiao,
J. M. Tetrahedron 2005, 61, 9902-9907 See also:(e) Deeth, R. J.; Smith, A.;
Brown, J. M. J. Am. Chem. Soc. 2004, 126, 7144–7151. We thank a referee for
calling this work to our attention.
Acknowledgment. We thank the Spanish Ministerio de
Ciencia y Tecnolog´ıa (Grant CTQ2004-04901, FEDER) for
financial support. C.A.C. and O.J.P. also wish to acknowledge
Colciencias and Universidad Nacional de Colombia for a
Fellowship during their stay at UPV.
J. Org. Chem. Vol. 73, No. 13, 2008 5197