N-acyliminium ion cyclisation versus rearrangement. The synthesis of 13,13-dimethylberberines and 3,4-dimethylisoquinolin-1-ones

Article abstract of DOI:10.1016/S0040-4039(00)00081-2

The regioselective reduction of a range of N-substituted-4,4- dimethylhomophthalimide derivatives gave the related carbinol amides that function as acyliminium ion precursors in the presence of Lewis or protic acids; the fate of the acyliminium ions is de

Full text of DOI:10.1016/S0040-4039(00)00081-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1993–1996
N-Acyliminium ion cyclisation versus rearrangement. The
synthesis of 13,13-dimethylberberines and
3,4-dimethylisoquinolin-1-ones
Harry Heaney ∗ and Mutasem O. Taha
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
Received 18 November 1999; accepted 11 January 2000
Abstract
The regioselective reduction of a range of N-substituted-4,4-dimethylhomophthalimide derivatives gave the
related carbinol amides that function as acyliminium ion precursors in the presence of Lewis or protic acids; the
fate of the acyliminium ions is determined in part by the nucleophilicity of the β-arylethyl group on nitrogen, the
electrophile used to generate the ion, and the precise reaction conditions and led either to cyclisation reactions or
methyl migration. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amido-alcohols; cyclisation; diastereoselection; nitrogen heterocycles.
The chemistry of acyliminium ions has been studied in considerable detail during the past two
decades,1 and the method continues to attract considerable attention.2 A number of research groups
have used the chemistry of acyliminium ions in routes to alkaloids or in the synthesis of compounds
with potential biological activity.3 Other targets have included isoquinolones by Friedel–Crafts
amidoacylation reactions,4a and antagonists of platelet aggregation.4b Our interest in this area is
concerned with both mechanistic and synthetic applications of acyliminium ions.5 Our most recent work
has been concerned with ring annelated tetrahydroisoquinolin-1[2H]-ones in which a key synthetic step
involved 1,2-alkyl-shifts involving cations derived from 4,4-dialkyl-3-hydroxy-3,4-dihydroisoquinolin-
1[2H]-one derivatives.5c A limited number of cyclisation reactions of N-β-arylacyliminium ions
have been reported.6 We now describe the use of a number of protic and Lewis acids in reactions
of carbinolamides that result in the formation of 13,13-dimethylberberine derivatives and 3,4-
dimethylisoquinolones.
The carbinolamides were prepared in three steps from commercially available homophthalic
anhydride. Heating the anhydride with a variety of arylalkylamines at 200°C for 90–120 min gave
the homophthalimide derivatives (1a–e) in yields ranging from 31 to 92%. The methylation of the
compounds (1a–e) was carried out in aqueous ethanolic sodium hydroxide solution with an excess of
∗
Corresponding author. Fax: 44 + 1509 223925; e-mail: h.heaney@lboro.ac.uk (H. Heaney)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00081-2
tetl 16359

1994
methyl iodide and gave the 4,4–dimethyl-3,4-isoquinolin-1[2H],3[4H]-dione derivatives (2a–e) in yields
ranging from 74 to 95%.† The regioselective reduction of the compounds (2a–e) were carried out using
an excess of NaBH4 in ethanol at −7°C followed by extraction after the addition of sodium hydrogen
carbonate and gave the carbinolamides (3a–e) in 21 to 85% yields. The homophthalimide (1e) and the
carbinolamide (3e) were those associated with the lowest yields.
The iminium ion is formed particularly easily from the carbinolamide 3c as evidenced by the partial
conversion of a solution of 3c in DMSO into 4 in 11% yield over a period of 10 days. When the
carbinolamide 3c was allowed to stand with aluminium chloride in THF at 0°C for 1 h it was converted
into the β-carboline derivative 4 in 87% yield. On the other hand, the products formed in reactions of the
carbinolamides 3a and 3b were found to depend on the reaction conditions used. When the carbinolamide
3a was allowed to react with either aluminium chloride or bromide a mixture of the berberine derivative
5a‡ and the isoquinolone 6a§ was formed in ratios¶ that were dependent on the choice of reaction
temperature and solvent. In view of the low solubility of aluminium chloride at low temperatures in
either dichloromethane or o-dichlorobenzene we used aluminium bromide as the preferred Lewis acid.
At low temperatures the compound 5a was the major product while at high temperatures the compound 6a
predominated. Thus at −5°C in o-dichlorobenzene the ratio of 5a to 6a was 7:3 while in dichloromethane
the ratio was 9.5:0.5. At ambient temperatures the ratios were almost 1:1 but at 180°C using either
aluminium bromide or aluminium chloride as the Lewis acid the ratio of 5a to 6a was 0.6:9.4. Although
the reactions leading to the two types of products are clearly irreversible the results suggest that the
transition state leading to 5a is early on the reaction coordinate while that leading to 6a is a late transition
state. Global energy calculations, conducted using SYBYL, showed that the minimum energies for 5a
and 6a are 2.98 and 0.28 kJ/mol, respectively, thus supporting the view that although 5a is kinetically
accessible, 6a is the thermodynamically preferred product.
†
New compounds have been fully characterised by elemental analysis or by accurate mass measurement of the molecular
ion by high resolution mass spectrometry and by spectroscopic methods including appropriate H and 13C NMR studies on
1
homogeneous material and by infrared measurements.
‡
M+ 277.1468, C19H19NO requires 277.1467: νmax: 2955, 1647, and 1602 cm−1: δH 250 MHz (CDCl3) 0.90 (s, 3H, Me),
1.40 (s, 3H, Me), 2.72–3.0 (m, 3H), 4.81 (s, 1H), 4.97–5.04 (m, 1H), 7.17–7.48 (m, 7H), and 8.12–8.16 (m, 1H) ppm: δC 62.8
MHz (CDCl3) 23.07 (Me), 23.79 (Me), 29.97 (CH2), 39.56 (CH2), 40.70 (C), 64.88 (CH), 123.35 (CH), 125.23 (CH), 126.84
(CH), 127.27 (CH), 128.24 (C), 128.47 (CH), 128.98 (CH), 130.13 (CH), 131.76 (C), 132.01 (CH), 138.61 (C), 147.68 (C), and
164.38 (C_O) ppm. DEPT, COSY 45, and 1H–13C HETCOR experiments support the assignments.
§
M+ 277.1458, C19H19NO requires 277.1467: νmax: 3050,1645, and 1614 cm–1: δH 250 MHz (CDCl3) 2.32 (s, 3H, Me),
2.40 (s, 3H, Me), 3.01–3.07 (m, 2H), 4.33–4.40 (m, 2H), 7.27–7.69 (m, 8H), and 8.49–8.52 (m, 1H) ppm: δC 100.5 MHz
(CDCl3) 13.75 (Me), 16.22 (Me), 34.79 (CH2), 46.34 (CH2), 109.01 (C), 122.41 (CH), 124.39 (C), 125.52 (CH), 126.37 (CH),
127.81(CH), 128.33 (2×CH), 128.41 (2×CH), 131.90 (CH), 134.82 (C), 136.95 (C), 138.48 (C), and 162.18 (C_O) ppm.
DEPT, COSY 45, and 1H–13C HETCOR experiments support the assignments.
¶
The ratios of mixtures of products were estimated from 1H NMR spectra of crude reaction mixtures.

1995
Reactions involving the carbinolamide 3b showed a different trend. The electron releasing methoxy
group at the 3-position in the carbinolamide 3b clearly promotes the cyclisation pathway both at ambient
and elevated temperatures when only one equivalent of aluminium bromide was used. The yields of
5b and 6b were 72% and 20%, respectively, at ambient temperature in dichloromethane and 78% and
22%, respectively, when the reaction was carried out at 180°C in o-dichlorobenzene. On the other hand
reactions carried out at −5°C with either 1 or 3 mol equivalents of aluminium bromide or with 3 mol
equivalents of aluminium bromide at ambient temperatures strongly favour the migration route to the
isoquinolone derivative 6b. A reaction carried out at −5°C was incomplete after 2 h but the isoquinolone
derivative 6b was the only product formed in 42% yield whereas at ambient temperature the compound
6b was formed in a quantitative yield after 2 h. These results clearly reflect the ability of aluminium
bromide to complex with the oxygen atoms that are present in the 3,4-dimethoxyphenyl residue and
thereby reduce the nucleophilicity of the aryl residue. Similar effects have been noted in connection with
Friedel–Crafts acylation reactions of a range of benzene derivatives that carry ortho-oxygen substituents.7
We were also interested to investigate possible diastereoselectivity effects in the cyclisation reactions
and selected for that purpose the carbinolamide 3e that was prepared starting from the ethyl ester of
tryptophan. The β-carboline derivative 7 was isolated in 77% yield as a single diastereomer when a
solution in CH2Cl2 was treated with a catalytic amount of hydrogen chloride. The gross structure was
confirmed†† using the usual spectroscopic methods and the configuration at the newly formed ring-
1
1
junction was established by a consideration of the H–1H spin–spin coupling constants and H–1H
NOESY experiments. We assume that the cis-relationship of the ethoxycarbonyl group and the hydrogen
at the newly formed ring-junction is formed with high diastereoselectivity as a result of rotation about
the bond between the β-indolyl residue and the remainder of the acyliminium ion fragment. Cyclisation
is presumed to be strongly favoured when rotation proceeds in a direction away from the ethoxycarbonyl
group that places the two hydrogen atoms trans to each other and the ethoxycarbonyl moiety in a pseudo-
axial position (Scheme 1).
Cyclisation reactions were not restricted to the formation of six-membered ring products. The conver-
sion of the carbinolamide 3d into the oxazepinoisoquinolone derivative 8 was achieved in modest yield
(32%) in a reaction carried out using titanium tetrachloride in dichloromethane, by starting at −78°C and
allowing the reaction mixture to warm slowly to ambient temperature (Scheme 2).
††
M+ 388.1784, C24H24N2O3 requires 388.1787: νmax: 3302 (br), 2978, 1734, 1638, and 1602 cm−1: δH 400 MHz (CDCl3)
0.82 (t, 3H, J=7.1 Hz), 0.94 (s, 3H, Me), 1.56 (s, 3H, Me), 3.00 (d×d, 1H, B of ABX, JAB=15.2 Hz, JBX=5.4 Hz), 3.45 (d×d,
1H, A of ABX, JAB=15.2 Hz, JAX=1.8 Hz), 3.77–3.86 (m, 2H), 5.02 (s, 1H), 5.85 (dxd, X of ABX, JAX=1.8 Hz, JBX=5.4 Hz),
7.02–7.47 (m, 7H), 8.12–8.14 (m, 1H), and 8.18 (br s, 1H, N–H) ppm: δC 62.8 MHz (CDCl3) 14.00 (Me), 23.14 (Me), 23.26
(Me), 23.67 (CH2), 40.35 (C), 52.32 (CH), 61.10 (CH), 61.21 (CH2), 110.35 (C), 111.03 (CH), 118.15 (CH), 119.78 (CH),
122.41 (CH), 123.43 (CH), 126.35 (C), 127.09 (CH), 127.47 (C), 129.54 (CH), 129.85 (C), 132.68 (CH), 136.34 (C), 147.09
1
(C), 165.65 (C=O), and 171.22 (C_O) ppm. DEPT, COSY 45, and H–13C HETCOR experiments support the assignments.
The relative orientations of the ethoxycarbonyl group and the vicinal methylene and bridgehead methine hydrogen atoms were
established by 400 MHz 1H–1H NOESY experiments carried out in CDCl3 at 298 K over a mixing time of 0.7 sec.

1996
Scheme 1.
Scheme 2.
Acknowledgements
We thank the University of Jordan and The British Council (M.O.T.) for financial support.
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