New 4-spiroannulated tetrahydroisoquinolines by a one-pot sequential procedure. Isolation and characterization of σ-alkylpalladium Heck intermediates

Article abstract of DOI:10.1021/ol061693c

A simple and efficient entry to new tetrahydroisoquinolines 4-spiroannulated to a five-membered heterocyclic ring has been achieved starting from secondary N-allylamines and involving sequential 2-iodobenzylation/ intramolecular Heck reaction/1,3-dipolar

Full text of DOI:10.1021/ol061693c

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4521-4524
New 4-Spiroannulated
Tetrahydroisoquinolines by a One-Pot
Sequential Procedure. Isolation and
Characterization of
Heck Intermediates
σ-Alkylpalladium
Egle M. Beccalli,† Gianluigi Broggini,*,‡ Michela Martinelli,†
Norberto Masciocchi,‡ and Silvia Sottocornola‡
Istituto di Chimica Organica “A. Marchesini”, Facolta` di Farmacia,
UniVersita` di Milano, Via Venezian 21, 20133 Milano, Italy, and
Dipartimento di Scienze Chimiche e Ambientali, UniVersita` dell’Insubria,
Via Valleggio 11, 22100 Como, Italy
gianluigi.broggini@uninsubria.it
Received July 10, 2006
ABSTRACT
A simple and efficient entry to new tetrahydroisoquinolines 4-spiroannulated to a five-membered heterocyclic ring has been achieved starting
from secondary N-allylamines and involving sequential 2-iodobenzylation/intramolecular Heck reaction/1,3-dipolar cycloaddition. A variety of
Heck cyclization conditions were surveyed. When using Pd(PPh3)4 as catalyst, stable
characterizated.
σ-alkylpalladium iodide complexes were isolated and
Spiroannulated isoquinolines are attractive compounds of
growing pharmaceutical interest as documented by many
recent patents. Their activity as neuropeptide Y antagonists,
SK channel blockers, and Mas receptor ligands make them
useful cardioprotective or neuroprotective agents.1
Due to our research interest concerning synthesis of
nitrogenated heterocycles,2,3 we envisioned the possibility
of assembling spirocompounds of type A according to the
retrosynthetic sequence described in Scheme 1, namely
through a tandem process involving intramolecular Heck
reaction and intermolecular 1,3-dipolar cycloaddition. Al-
† Universita` di Milano.
‡ Universita` dell’Insubria.
(2) For intramolecular Pd-catalyzed reactions, see: (a) Beccalli, E. M.;
Broggini, G.; Marchesini, A.; Rossi, E. Tetrahedron 2002, 58, 6673. (b)
Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003,
68, 7625. (c) Beccalli, E. M.; Broggini, G.; Paladino, G.; Penoni, A.; Zoni,
C. J. Org. Chem. 2004, 69, 5627. (d) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Paladino, G.; Zoni, C. Eur. J. Org. Chem. 2005, 2091. (e)
Abbiati, G.; Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.
Synlett 2006, 73. (f) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino,
G.; Rossi, E. Synthesis 2006, 2404.
(3) For 1,3-dipolar cycloadditions, see: (a) Broggini, G.; La Rosa, C.;
Zecchi, G. Synlett 1995, 1208. (b) Broggini, G.; Zecchi, G. Synthesis 1999,
905. (c) Arnone, A.; Broggini, G.; Passarella, D.; Terraneo, A.; Zecchi, G.
J. Org. Chem. 1998, 63, 9279. (d) Beccalli, E. M.; Broggini, G.; La Rosa,
C.; Passarella, D.; Pilati, T.; Terraneo, A.; Zecchi, G. J. Org. Chem. 2000,
65, 8924. (e) Broggini, G.; Chiesa, K.; De Marchi, I.; Martinelli, M.; Pilati,
T.; Zecchi, G. Tetrahedron 2005, 61, 3525.
(1) (a) Boatman, D. P.; Adams, J. W.; Moody, J. V.; Babych, E. D.;
Schrader, T. O. PCT Int. Appl. WO 2005063745, 2005; Chem. Abstr. 2005,
143, 133293. (b) Takamuro, I.; Homma, K.; Ishida, A.; Taniguchi, H.;
Onoda, Y. Jpn. Kokai Tokkyo Koho JP 2004115450, 2004; Chem. Abstr.
2004, 140, 332509d. (c) Saito, S.; Umemiya, H.; Suga, Y.; Sato, M.;
Kawashima, N. PCT Int. Appl. WO 2003095427, 2003; Chem. Abstr. 2003,
139, 395821z. (d) Fukami, T.; Nonoshita, K.; Sagara, T.; Kishino, H. PCT
Int. Appl. WO 2003014083, 2003; Chem. Abstr. 2003, 138, 170086. (e)
Takamuro, I.; Homma, K.; Ishida, A.; Taniguchi, H.; Onoda, Y. PCT Int.
Appl. WO 2002079189, 2002; Chem. Abstr. 2002, 137, 294881. (f) Fukami,
T.; Kanatani, A.; Ishihara, A.; Ishii, Y.; Takahashi, T.; Haga, Y.; Sakamoto,
T.; Itoh, T. PCT Int. Appl. WO 2001014376, 2001; Chem. Abstr. 2001,
134, 207809. (g) Poindexter, G. S.; Antal, I.; Giupponi, L. M.; Stoffel, R.
H.; Bruce, M. PCT Int. Appl. WO 2001013917, 2001; Chem. Abstr. 2001,
134, 193416.
10.1021/ol061693c CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/02/2006

amines 2a-d in the presence of TEA in DMF at 60 °C for
45 min was followed by the addition of Pd(OAc)2 (0.05
equiv), Na2CO3 (2 equiv), and n-Bu4NCl (1 equiv) to
promote the desired Heck reaction. These conditions match
those reported for a similar reaction.9 After heating at 120
°C for 6 h, the nitrile oxide 3 (1.2 equiv) was added as a
potential reaction partner toward the intermediate 4-hexo-
methyleneisoquinolines.
Scheme 1. Retrosynthetic Analysis of 4-Spiroannulated
Tetrahydroisoquinolines
4-Spiroannulated tetrahydroisoquinolines 4a-d were iso-
lated as the final products. In line with the literature data
dealing with nitrile oxide cycloadditions to 1,1-disubstituted
ethylenes,10 total regioselectivity (by NMR) was observed.
The 4-5′ junction of the isoquinoline-isoxazole system was
1
established by H and 13C chemical shifts as well as by
geminal coupling constants (greater than 18 Hz)11 of the
methylenic group of the isoxazole ring, which are only
compatible with the 4-position. It must be noted that, when
two dipolarophilic sites were present in the substrate (2b),
no diaddition product was isolated. The overall yields of the
one-pot protocol were in the range of 22-28%.
Despite obtaining the desired products, the observed yields
seemed somewhat unsatisfactory. This prompted us to a
detailed investigation of the single steps of the sequence and,
in particular, to conduct a deeper search for Heck conditions.
For this purpose, we isolated the intermediate 5a in quantita-
tive yield and submitted it to a variety of conditions
potentially suitable for the Heck reaction. The results are
collected in Table 1, where entry 1 refers to our initial
experiment. Under these conditions, the cyclized product 6a
was obtained in 34% yield along with sizable amounts of
though intramolecular Heck couplings4 have found a broad
range of applications in tandem processes,5 to the best of
our knowledge such combined methods are the object of only
one literature report.6 The derivatives B, built from C under
Heck conditions, should be easily and variously spiroannu-
lated at the exocyclic C-C double bond by exploiting the
well-established versatility of 1,3-dipolar cycloadditions for
the construction of five-membered heterocyclic rings.7 The
1,1-disubstitution of the dipolarophile should induce complete
regioselectivity in the cycloadditive process. As an example,
nitrile oxides were the 1,3-dipolar species leading to spiro-
[isoquinoline-4,5′-isoxazole] structures.
Aiming for the above target, we selected as suitable
starting materials 2-iodobenzyl bromide (1), a number of
commercially available allylamines (2a-d), and the long-
known 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide8 (3)
(Scheme 2). The latter 1,3-dipolar substrate was chosen due
(4) (a) Link, J. T. Org. React. 2002, 60, 160. (b) Bra¨se, S.; de Meijere,
A. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004; Chapter 5. (c) Goossen, L.;
Baumann, K. In Handbook of C-H Transformation; Dyker, A., Ed.; Wiley-
VCH: Weinheim, 2005; Chapter 2.1. (d) Beletskaya, I. P.; Cheprakov, A.
V. Chem. ReV. 2000, 100, 3009. (e) Phan, N. T. S.; Van Der Sluys, M.;
Jones, C. W. AdV. Synth. Catal. 2006, 348, 609.
(5) For examples of tandem processes involving intramolecular Heck
reactions, see: (a) Negishi, E.-i; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F.
Chem. ReV. 1996, 96, 365. (b) Shibasaki, M.; Vogl, E. M.; Ohshima, T.
AdV. Synth. Catal. 2004, 346, 1533. (b) Dounay, A. B.; Overman, L. E.
Chem. ReV. 2003, 103, 2945. (c) Artman, G. D., III; Weinreb, S. M. Org.
Lett. 2003, 5, 1523. (d) Harrowen, D. C.; Woodcock, T.; Howes, P. D.;
Howes, P. D. Tetrahedron Lett. 2002, 43, 9327. (e) Grigg, R.; Sridharan,
V.; York, M. Tetrahedron Lett. 1998, 39, 4139. (f) Maddaford, S. P.;
Andersen, N. G.; Cristofoli, W. A.; Keay, B. A. J. Am. Chem. Soc. 1996,
118, 10766.
Scheme 2. One-Pot Synthesis of
Spiro[isoquinoline-4,5′-isoxazole] Compounds
(6) Grigg, R.; Millington, E. L.; Thornton-Pett, M. Tetrahedron Lett.
2002, 43, 2605.
(7) (a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New
York, 1984; Vols. I and II. (b) Padwa, A.; Pearson, W. H. Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Wiley: New York, 2003.
(8) Beltrame, P.; Veglio, C.; Simonetta, M. J. Chem. Soc. B 1967, 867.
(9) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291.
(10) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: New York, 1988. (b) Curran, D. P. In AdVances
in Cycloadditions; Curran, D. P., Ed.; JAI Press: London, 1988; Vol. I, pp
129-189. (c) Gru¨nanger, P.; Vita-Finzi, P. Isoxazoles; Wiley: New York,
1991.
(11) (a) Boyle, P. H.; O’Mahony, M. J.; Cardin, C. J. J. Chem. Soc.,
Perkin Trans. 1, 1984, 593. (b) Broggini, G.; Bruche´, L.; Zecchi, G.; Pilati,
T. J. Chem. Soc., Perkin Trans. 1 1990, 533. (c) Broggini, G.; Zecchi, G.
J. Chem. Soc., Perkin Trans. 1 1991, 1843. (d) Occhiato, E. G.; Guarna,
A.; Brandi, A.; Goti, A.; De Sarlo, F. J. Org. Chem. 1992, 57, 4206. (e)
Broggini, G.; Molteni, G.; Zecchi, G. J. Org. Chem. 1994, 59, 8271.
(12) Crystal data: triclinic, space group P-1 (No. 2), a ) 9.458(2) Å; b
) 11.332(2) Å; c ) 13.604(2) Å, R ) 76.51(1)°; â ) 86.68(2)°; γ ) 82.32-
(2)°; V ) 1404.6(4) Å, Z ) 2, CCDC 613934.
to its stability that seemed essential to realize a sequential
one-pot process. As depicted in Scheme 2, the treatment of
equimolar amounts of 2-iodobenzyl bromide (1) and allyl-
4522
Org. Lett., Vol. 8, No. 20, 2006

Table 1. Reaction Conditions and Yields for Intramolecular Heck Reaction of 5a
entry
catalysta
additive/igandb
basec
solvent
T (°C)
time (h)
yields of 6a (%)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3‚CHCl3
Pd(PPh3)4
Bu4NCl
Bu4NCl
PPh3
Na2CO3
Na2CO3
Cs2CO3
Et3N
DMF
NMP
DMF
DMF
CH3CN
120
120
120
120
reflux
6
8
6
5
24
34
26
55
61
12
PPh3
Et3N
a Pd(OAc)2, 5 mol %; Pd2(dba)3‚CHCl3, 2.5 mol %; Pd(PPh3)4, 10 mol %. b n-Bu4NCl, 1 equiv; PPh3, 0.2 equiv. c Na2CO3, 2 equiv; Cs2CO3, 2 equiv;
Et3N, 3 equiv.
2,4-dimethylisoquinolin-1(2H)-one (7) and 4-formyl-2-me-
thylisoquinolin-1(2H)-one (8) (Scheme 3). The formation of
Further evidence is now presented about the unexpected
outcome achieved when attempting the Heck cyclization of
5a using Pd(PPh3)4 as catalyst. In addition to the cyclized
product 6a and to a large amount of unreacted allylamine
5a (47%), a third product was isolated by silica gel column
Scheme 3. Synthesis of Spiro[isoquinoline-4,5′-isoxazole] 4a
1
chromatography. The H and 13C NMR analysis suggested
with Isolation of the Intermediates
the structure of a Pd complex containing a unity of PPh3.
The same type of product was obtained when the reaction
was repeated on the allylamines 5b-c (Scheme 4). Two-
Scheme 4. Synthesis and Conversion of Heck Intermediates
9a-c
such byproducts is probably due to the thermally induced
isomerization of 6a to 1,2-dihydro-2,4-dimethylisoquinoline,
which in turn could be susceptible to air oxidation. As a
support to this result, we demonstrated that the prolonged
heating of 6a in DMF at 120 °C led to a mixture containing
7 and 8. It is known that, under the same conditions, the
2-unsubstituted term of general formula 6 underwent an
oxidative aromatization to 4-methylisoquinoline.9
Replacement of DMF with NMP (entry 2) did not give
an improved outcome, while the formation of 6a was
markedly improved when using the same catalyst in DMF
at 120 °C in the presence of Cs2CO3 as a base and PPh3 as
a ligand (entry 3). The best result was observed under
Pd2(dba)3‚CHCl3 catalysis in DMF at 120 °C in the presence
of Et3N and PPh3 (entry 4). Conversely, the extent of the
Heck reaction dramatically fell when Pd(PPh3)4 was used
as catalyst in refluxing CH3CN in the presence of only Et3N
(entry 5). At this point, we first verified that the reaction of
6a with 3 took place in good yield (72%) and then we
realized for each substrate the one-pot sequential procedure
under the different Heck conditions reported in Table 1. The
best overall yields, ranging from 30 to 45%, were achieved
under the conditions of entry 3.
dimensional NMR experiments (i.e., HETCOR and COSY),
taken on the compound arising from the diallylamine 5b,
were consistent with a single diastereoisomer of a stable
σ-alkyl-Pd-PPh3-iodine complex. X-ray diffractrometric
analysis12 unambiguously confirmed the bridged structure
9b, containing a five-membered nitrogenated palladacycle
with trans disposition of the iodine atom and the methylenic
group (see ORTEP representation in Figure 1). Moreover,
when the reactions were performed with a stoichiometric
amount of Pd(PPh3)4, the palladacycles 9a-c were isolated
in 55-66% yield. The NMR spectral data indicate the
products 9a and 9c were formed diastereoselectively. These
complexes were found to be highly stable toward air,
moisture, heat (ethanol at reflux) and bases (i-Pr2NEt and
pyridine in CHCl3). The capture of σ-alkylpalladium Heck
(13) (a) Clique, B.; Fabritius, C.-H.; Couturier, C.; Monteiro, N.; Balme,
G. Chem. Commun. 2003, 272. (b) Oestreich, M.; Dennison, P. R.; Kodanko,
J. J.; Overman, L. E. Angew. Chem., Int. Ed. 2001, 40, 1439. (c)
Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.;
Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C.
A.; Coburn, C. A.; Di Grandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843.
(d) McCrindle, R.; Ferguson, G.; McAlees, A. J.; Arsenault, G. J.; Gupta,
A.; Jennings, M. C. Organometallics 1995, 14, 2741. (e) Kwok, D.-I.; Farr,
R. N.; Daves, G. D., Jr. J. Org. Chem. 1991, 56, 3711.
Org. Lett., Vol. 8, No. 20, 2006
4523

ation. Moreover, a beneficial stabilization of the intermediate
complexes through coordination of the metal with nitrogen
atom is reported.14 Only refluxing 9a-c in CH3CN and in
the presence of Et3N promotes their conversion to 6a-c.
In conclusion, starting from 2-iodobenzyl bromide and
secondary N-allylamines, we have successfully developed
an effective one-pot, three-component procedure providing
new spiro[isoquinoline-4,5′-isoxazole] structures. The pro-
cedure is based on a sequential intramolecular Heck reaction
and a regioselective intermolecular 1,3-dipolar cycloaddition.
On considering that the sequence involves the overall
formation of one carbon-nitrogen, two carbon-carbon, and
one carbon-oxygen bonds, the yields can be considered
satisfactory.
Also, we have brought to light the first example of the
systematic isolation and characterization of the σ-alkylpal-
ladium complex intermediate in an intramolecular Heck
reaction promoted by Pd(PPh3)4.
Figure 1. ORTEP drawing of compound 9b. Thermal ellipsoids
are drawn at the 50% probability level. Hydrogen atoms are given
with arbitrary radii.
Further work is ongoing to apply the same strategy to a
wider range of 2-halo-substituted aryl systems bearing an
allyl moiety and to other 1,3-dipoles.
intermediates with inhibition of â-hydride elimination is not
unprecedented in the literature, but there are only a few
examples.13 As highlighted by Balme’s work,13a an analogous
bridged palladacycle was isolated only when supported on
a naphthyl nucleus. The results of our experiments, to the
best of our knowledge, constitutes the first example of the
systematic isolation of the σ-alkylpalladium intermediates
in intramolecular Heck processes. The marked stability of
the complexes 9a-c may be due to the harsh constraint of
the palladacycle imposed by the bridged junction, which
hinders the cisoid conformation essential to â-hydride elimin-
Acknowledgment. Thanks are due to the Ministero
dell’Istruzione, dell’Universita` e della Ricerca for financial
support. We are also grateful to the Centro Interuniversitario
sulle Reazioni Pericicliche and to Fondazione CARIPLO.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for compounds 4a-d, 6a-c, and 9a-c. Crystal data and
experimental procedures for the X-ray structure of 9b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Burke, B. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126, 16820.
(b) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123,
8217. (c) Buezo, N. D.; Manchen˜o, O. G.; Carretero, J. C. Org. Lett. 2000,
2, 1451.
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