Acid-catalyzed cyclization of acyliminium ions derived from allenamides. A new entry to protoberberines

Article abstract of DOI:10.1016/j.tetlet.2007.02.056

Under mild acidic conditions, N-(ω-phenylalkyl)allenamides can yield stabilized acyliminium ions which through intramolecular aromatic electrophilic substitution furnish 1-vinylisoindolines and isoquinolines. Stereoelectronic and entropic effects in these

Full text of DOI:10.1016/j.tetlet.2007.02.056

Tetrahedron Letters 48 (2007) 2741–2743
Acid-catalyzed cyclization of acyliminium ions derived from
allenamides. A new entry to protoberberines
*
´
´
´
´
´
A. Navarro-Vazquez, D. Rodrıguez, M. F. Martınez-Esperon, A. Garcıa,
*
´
´
C. Saa and D. Domınguez
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Facultad de Quı´mica, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Received 23 January 2007; accepted 9 February 2007
Available online 15 February 2007
Abstract—Under mild acidic conditions, N-(x-phenylalkyl)allenamides can yield stabilized acyliminium ions which through intra-
molecular aromatic electrophilic substitution furnish 1-vinylisoindolines and isoquinolines. Stereoelectronic and entropic effects in
these cyclizations have been evaluated by DFT computations. The 1-vinylisoquinolines obtained have been employed as key inter-
mediates in the synthesis of the protoberberine skeleton.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Allenamide chemistry1 has received considerable atten-
tion in recent years,2 with exploration of the reactivity
of allenamides in transition-metal catalyzed cyclization,3
[2+2] and inverse demand [4+2] cycloadditions,4 and
other cyclization reactions.5 Allenamides (3) are com-
monly prepared by a tandem reaction in which conden-
sation of propargyl bromide with a secondary amide (1)
is followed by base-catalyzed isomerization of the result-
ing propargylamide (2) (Scheme 1), although under
these conditions the resulting allenamides sometimes
evolve further to ynamides.2a Due to allylic stabilization
of the intermediates, these electron-deficient allenamines
are highly susceptible to nucleophilic, electrophilic, and
even radical addition6 at the central sp carbon atom.
ment of an appropriate allenamide with trifluoroacetic
acid. The reaction was developed and investigated using
allenamides 3a–e (Table 1), which were prepared in
50–90% overall yield by reaction of the corresponding
amines with an acylating agent followed by treatment
with propargyl bromide in the presence of a base.8
Treatment of allenamides 3 with a catalytic amount of
TFA in dichloromethane at room temperature afforded
the vinyl-substituted heterocyclic compounds 5 in mod-
erate to good yields,9 presumably through protonation
of the allenamide followed by intramolecular electro-
philic aromatic substitution on the electron-rich arene
of the resulting acyliminium ion (4) (Scheme 2). That
these reactions take place under such mild conditions
can undoubtedly be attributed to the allylic nature of
the intermediate cations 4.
In this Letter we describe a new cyclization reaction
based on the formation of an acyliminium ion7 by treat-
In the first of these cyclizations, treatment of benzylallen-
amide 3a with a catalytic amount of TFA afforded the
Table 1. Yields in the preparation and acid-catalyzed cyclization of
allenamides 3a–e
Scheme 1.
Compound
n
R1
R2
% Yield of 3 % Yield of 5
a
b
c
d
e
0
1
1
1
2
MeO
MeO
H
MeO 2-I-Phenyl
MeO
H
H
H
50
85
63
74
81
22
67
—
78
—
Keywords: Allenamides; Acyliminium; Isoindolines; Isoquinolines;
Protoberberines.
*
Corresponding authors. Fax: +34 981 595012 (D.D.); e-mail
addresses: qomingos@usc.es; qoajnv@usc.es
H
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.056

2742
A. Navarro-Va´zquez et al. / Tetrahedron Letters 48 (2007) 2741–2743
Scheme 2.
Table 2. Activation barrriers (kcal/mol) and relevant geometric parameters for the cyclization of allenamides 3a, 3b and 3e
Structure
TS-4a
DHy0
15.8
0.9
DGy298:15 (Gas-phase)
DGy298:15 (CH2Cl2)
17.4
4.4
17.3
9.0
TS-4b
TS-4e
7.5
12.0
18.8
desired vinyl isoindoline 5a, but only in low yield (22%).
Much better yield was achieved with the phenethyl com-
pounds 3b and 3d, which afforded vinyl isoquinolines 5b
and 5d in 67% and 78% yield, respectively.10 That the
aromatic ring must be electron-rich was shown by the
failure of allenamide 3c to cyclize even under harsher
conditions (50% TFA, DMF, 70 ꢁC). The homologous
compound 3e also failed to cyclize under the standard
reaction conditions, and raising the temperature to
60 ꢁC resulted in hydrolysis to the secondary amide.
TS-4a with a poor alignment between reaction centres
(H = 122.1ꢁ), and 12.0 kcal/mol in TS-4e, in which
H = 109.5ꢁ but greater crowding is present due to an
unfavourable axial disposition of the amide group in
the crown-chair transition state (geometries can be
examined in Supplementary data). When solvation is
taken into account, the barriers in TS-4b and TS-4e
are increased due to 4b and 4e being more easily
solvated than the transition states, but the barrier in
TS-4a remains virtually unchanged because solvation
of 4a is also inefficient. Unfavourable entropic effects
also increase with the length of the phenylalkyl chain
of the acyliminium ions, DGy298:15 ꢀ DH0y being 1.6, 3.5
and 4.5 kcal/mol for TS-4a, TS-4b and TS-4e,
respectively.14
Suspecting that the differences in behaviour among
homologues 3a, 3b and 3e might be due to stereoelec-
tronic constraints in the aromatic electrophilic substitu-
tion step, we investigated this step by computing
geometries and energies for intermediates 4a,b,e and
transition structures TS-4a,b,e at the B3LYP11/6-
31+G* level. Given their cationic nature, solvation
effects were taken into account by performing B3LYP/
6-31+G* CH2Cl2 PCM12 single-point computations on
the optimized gas-phase structures (Table 2). All compu-
tations were performed using the GAUSSIAN03
package.13
Finally we observed that the tetracyclic unit of the pro-
toberberine skeleton15 ought to be easily constructed by
a 6-exo Heck reaction of an ortho-iodobenzamide such
as 5d (Scheme 3), as indeed proved to be the case. When
vinylisoquinoline 5d was heated at 100 ꢁC in DMF in
the presence of catalytic Pd(OAc)2, K2CO3 as a base
and Et4NBr as an additive, methylene protoberberine
6d was obtained in 70% yield.16,17
The computations clearly show that formation of the
six-membered ring of 5b is specially favoured by its
allowing perfect alignment of the reaction centres for
tetrahedral attack of the positively charged carbon on
the arene (H = 109.4ꢁ) in a chair-like conformation.
Thus the gas-phase activation barrier DGy298:15 is only
4.4 kcal/mol in TS-4b, as against 17.4 kcal/mol in
In conclusion, allenamides can be used to prepare 1-
vinylisoindolines or isoquinolines via acyliminium ions
under very mild conditions. The isoquinolines can serve
as intermediates in a new synthesis of functionalized
protoberberines.
Acknowledgements
Support of this work by grants from the Spanish Minis-
try of Education and Science in collaboration with
ERDF (Project CTQ2005-02338) and from the Xunta
de Galicia (Project PGIDIT06PXIC209067PN) is grate-
fully acknowledged. We also thank the CESGA for
computer time.
Scheme 3.

A. Navarro-Va´zquez et al. / Tetrahedron Letters 48 (2007) 2741–2743
2743
112.2 (CH), 111.9 (CH), 111.2 (2 · CH), 101.1 (CH), 97.5
(CH), 92.7 (C), 92.4 (C), 87.1 (CH2), 87.0 (CH2), 55.9
(CH3O), 55.9 (CH3O), 55.9 (CH3O), 55.7 (CH3O), 49.2
(CH2), 45.5 (CH2), 33.9 (CH2), 32.7 (CH2). IR (film,
cmꢀ1): 3049, 2940, 2833, 2359, 1647,1514.
Supplementary data
Cartesian coordinates and energies for all computed
structures. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2007.02.056.
9. All new compounds were fully characterized spectroscop-
ically and had satisfactory elemental analyses or HRMS
data.
10. Typical procedure for cyclization of allenamides: TFA
(17 lL) was added to a solution of allenamide 3d (600 mg,
1.34 mmol) in 40 mL of dry dichloromethane, and the
mixture was stirred at room temperature for 24 h. Extra
TFA (20 lL) was added, and stirring was continued for a
further 5 days. The reaction mixture was then washed with
NaHCO3 and water, and the organic solvent dried and
evaporated. Purification by flash chromatography on silica
gel (1:1 hexanes/EtOAc) gave isoquinoline 5d as a foam
(470 mg, 78%). 1H NMR (d ppm): (mixture of a major and
minor rotamers) 7.85 (d, J = 7.8 Hz, HM), 7.80 (d,
J = 6.9 Hz, Hm), 7.41 (m, HM+Hm), 7.34–7.20 (m), 7.15
(m, HM+Hm), 6.69 (s, HM+Hm), 6.62 (s, HM), 6.45 (s,
Hm), 6.26–6.00 (m, HM+2Hm), 5.93–5.80 (m, Hm), 5.36–
5.14 (m), 5.00–4.78 (m), 3.90 (s, 3HM+3Hm, 2 · CH3O),
3.89 (s, 3HM, CH3O), 3.82 (s, 3Hm, CH3O), 3.81 (m, Hm),
3.61–3.11 (m), 2.87–2.57 (m). MS (m/e %): 449 (M+, 3),
322 (M+ꢀI, 100), 231 (92).
References and notes
1. For the first allenamides see: (a) Dickinson, W. B.; Lang,
P. C. Tetrahedron Lett. 1967, 8, 3035; (b) Overmann, L.
E.; Marlowe, C. K.; Clizbe, L. A. Tetrahedron Lett. 1979,
20, 599.
2. For reviews on allenamides see: (a) Wei, L.-L.; Xiong, H.;
Hsung, R. P. Acc. Chem. Res. 2003, 36, 773; (b) Saalfrank,
R. W.; Lurz, C. J. In Methoden Der Organischen Chemie
(Houben Weyl); Kropf, H., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1993; pp 3093–3102.
3. Gardiner, M.; Grigg, R.; Sridharan, V.; Vicker, R.
Tetrahedron Lett. 1998, 39, 435, and references cited
therein.
4. [2+2]: (a) Kimura, M.; Horino, Y.; Wakamiya, Y.;
Okajima, T.; Tamaru, Y. J. Am. Chem. Soc. 1997, 119,
10869, and references cited therein.; [4+2]: (b) Wei, L.-L.;
Xiomg, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron Lett.
1999, 40, 6903; (c) Kimura, M.; Wakamiya, Y.; Horino,
Y.; Tamaru, Y. Tetrahedron Lett. 1997, 38, 3963.
5. (a) Noguchi, M.; Okada, H.; Wantanabe, M.; Okuda,
K.; Nakamura, O. Tetrahedron 1996, 52, 6581; (b)
Kant, J.; Farina, V. Tetrahedron Lett. 1992, 33, 3559–
3563.
6. Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775.
7. (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367; For allenamide-derived acyliminium ions see: (b)
Berry, C. R.; Hsung, R. P.; Antoline, J. E.; Petersen, M.
E.; Challeppan, R.; Nielson, J. A. J. Org. Chem. 2005, 70,
4038.
11. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
12. Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55,
117.
13. Frisch, M. J. et al. GAUSSIAN03, Revision B. 05; Gaussian:
Wallingford, CT, 2004.
14. For proper computation of thermochemical properties,
free rotors should be considered explicitly. The entropy
penalty should therefore be higher than was computed
with the harmonic approximation used here.
15. For a recent synthesis of protoberberines, see: Orito, K.;
Satoh, Y.; Nishizawa, H.; Harada, R.; Tokuda, M. Org.
Lett. 2000, 2, 2535.
8. Typical procedure for the synthesis of allenamides: KOtBu
(490 mg, 4.01 mmol) and propargyl bromide (330 lL,
4.38 mmol) were added to a solution of N-(3,4-dimeth-
oxyphenethyl)-2-iodo benzamide (1.5 g, 3.67 mmol) in
6 mL of dry DMSO and the resulting black solution was
stirred at room temperature. Since after 1 h TLC still
showed two spots, a further 90 mg of KOtBu was added
and the reaction was continued until the complete
disappearance of the spot of lower Rf (6 h). The crude
reaction mixture was poured onto water, extracted with
EtOAc, the extract was dried with Na2SO4 and filtered,
and the solvent was removed under reduced pressure.
Purification by flash chromatography on silica gel (1:1,
hexanes/EtOAc) gave allenamide 3d as an amorphous
solid (1.21 g, 74%). 1H NMR (d ppm): (mixture of a major
and minor rotamers) 7.86 (d, J = 7.6 Hz, HM), 7.81 (d,
J = 7.6 Hz, Hm), 7.67 (t, J = 6.5 Hz, Hm, C@C@CH), 7.42
(t, J = 7.6 Hz, HM), 7.28 (t, J = 7.6 Hz, Hm), 7.21–7.03 (m,
2HM+2Hm), 6.86–6.82 (m, 2HM), 6.74–6.69 (m, HM+Hm),
6.47 (d, J = 8.1 Hz, Hm), 6.33–6.29 (m, HM+Hm), 5.54 (t,
J = 6.2 Hz, 2Hm, CH2@C@C), 5.40 (br s, 2HM,
CH2@C@C), 3.89 (s, 3HM, CH3O), 3.87 (s, 3HM,
CH3O), 3.84 (s, 3Hm, CH3O), 3.73 (s, 3Hm, CH3O), 4.1–
3.7 (br m, HM+2Hm), 3.51 (br m, Hm), 3.36 (br m, Hm),
2.98 (br m, 2HM), 2.75 (t, J = 7.4 Hz, HM). 13C NMR (d
ppm) 202.8 (C@C@C), 200.3 (C@C@C), 168.7 (C@O),
168.2 (C@O), 149.0 (C), 148.9 (C), 147.8 (C), 147.6 (C),
141.3 (C), 141.1 (C), 139.4 (CH), 138.9 (CH), 131.3 (C),
131.0 (CH), 130.5 (C), 130.2 (CH), 128.4 (CH), 127.9
(CH), 127.8 (CH), 127.7 (CH), 120.9 (CH), 120.8 (CH),
16. Procedure for the synthesis of 6d: Pd(OAc)2 (4 mg,
0.02 mmol), Et4NBr (35 mg, 0.17 mmol) and K2CO3
(58 mg, 0.43 mmol) were successively added to a solution
of vinylisoquinoline 5d (75 mg, 0.17 mmol) in 3 mL of dry
DMF. The mixture was heated under Ar at 100 ꢁC for
10 h, and then cooled down, poured onto water and
extracted with EtOAc. The organic extract was dried with
Na2SO4 and filtered, and the solvent was removed under
reduced pressure. Purification by flash chromatography on
silica gel (6:4 hexanes/EtOAc) gave protoberberine 6d as
an amorphous solid (38 mg, 70%). 1H NMR (d ppm): 8.14
(d, J = 7.1 Hz, 1H, Ar–H), 7.64–7.38 (m, 3H, Ar–H), 6.71
(s, 1H, Ar–H), 6.66 (s, 1H, Ar–H), 5.76 (s, 1H, C@CH),
5.43 (s, 1H, C@CH), 5.14 (s, 1H, CHN), 5.02–4.88 (m, 1H,
CH2), 3.86 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 3.20–3.03
(m, 2H, CH2), 2.82–2.67 (m, 1H, CH2). 13C NMR (d
ppm): 163.8 (C@O), 148.1 (C), 146.9 (C), 140.2 (C), 136.1
(C), 132.0 (CH), 128.7 (CH), 128.7 (CH), 128.2 (CH),
127.9 (C), 127.3 (C), 125.5 (C), 123.6 (CH), 115.1 (CH2),
111.7 (CH), 109.5 (CH), 61.0 (CH), 55.9 (CH3O), 55.8
(CH3O), 41.3 (CH2), 27.7 (CH2). MS (m/e %): 321 (100),
320 (38), 290 (60). IR (film cmꢀ1): 2937, 2833, 1650, 1641,
1514. Elem. Anal. Calcd for C20H19NO3: C, 74.75; H,
5.96; N, 4.36. Found: C, 74.47; H, 6.12; N, 4.09.
17. We also tried the cyclization under standard tin-mediated
radical conditions. Since amide 5d exists in solution as a
mixture of rotamers, the carbonyl group was first reduced
with AlH3/THF. However, treatment of the resulting
vinylisoquinoline with Bu3SnH/AIBN afforded only poly-
merization products.