A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion cyclisation

Article abstract of DOI:10.1039/c0ob00559b

The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of (di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary alkylamine was obtained. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c0ob00559b

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PAPER
A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion
cyclisation†
Frank D. King,* Abil E. Aliev, Stephen Caddick and D. A. Tocher
Received 10th August 2010, Accepted 24th November 2010
DOI: 10.1039/c0ob00559b
The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of
(di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary
alkylamine was obtained.
Table 1 Synthesis of substituted benzazocin-5-ones 2a–j
Introduction
Cpd. No.
R
T (h)a
Isolated yield (%)
We have an on-going interest in the synthesis of conformationally
restricted benzylamines as potential CNS drugs.1 We recently
described the synthesis of pyrrolo-benzazocin-7-ones via a triflic
acid-mediated cyclisation of acyliminium ions in which the
acyl group was exocyclic to the cyclic iminium ion precursor
(Scheme 1).2
2a
2b
2c
2db
2eb
2f
H
14-Cl
14-Br
13-Br
1
3
3
3
3
3
0.25
1
1
78
65
73
73
18
80
74
0
15-Br
13,15-di-Br
13,14-di-MeO
14-MeO
14-Me
2gc
2h
2i
80
0
2j
14-NO2
48
a Time of reaction in CHCl3, heated under reflux. b Two isomers formed
from reduction and cyclisation of N-(3-bromophenyl) butyl succinimide
in a total yield of 91%. c A single isomer was obtained.
Scheme 1 The exocyclic N-acyliminium ion cyclisation to pyrrolo-
benzazocin-7-ones.2
The success of this methodology prompted us to investigate
the triflic acid-mediated cyclisation of the endocyclic acyliminium
ion derived from 1, in which the acyl group is now within the
ring of the cyclic iminium ion precursor, for the synthesis of
pyrrolobenzazepin-5-ones 2 (Scheme 2). Such endocyclic acyli-
minium ion cyclisations have been reported for the synthesis of
tetrahydro-isoquinolinones and benzazepinones.3
Results and discussion
Scheme 2 The endocyclic N-acyliminium ion cyclisation for the synthesis
of benzazocinones 2a-j. Reagents and conditions: a) Ph3P, succinimide,
DEAD, b) NaBH4, KHCO3, c) CF3SO3H, CHCl3, heat.
The succinimides 1a–j were readily prepared either from the 4-
arylbutan-1-ols via a Mitsunobu reaction with dried succinimide4
or from the amines and succinic anhydride.5 Reduction with
NaBH4 in EtOH buffered with 15% H2O/KHCO3 gave the
hydroxyamides, which were cyclised using a 10 fold excess of
triflic acid in refluxing CHCl3 to give the pyrrolobenzazocin-5-
ones 2a–j (Table 1). For the bromo compounds 2c–e, we found
that borohydride reduction resulted in ~5% debromination and
so for these examples DIBAL was used for the reduction.6
As previously observed in related cyclisations,1,2 the p-methoxy
analogue failed to give any of the desired product. We believe
this is because of O-demethylation and subsequent reaction to
form an insoluble material. This cyclisation works well for mildly
deactivated phenyls, such as the dibromo 2f but not for the strongly
deactivated nitro 2j. At room temperature, the NMR spectra of
the pyrrolobenazocinones were often poorly resolved, with peak
broadening, and peaks were often missing in the 13C spectrum.
Department of Chemistry, University College London, 20 Gordon Street,
London, U.K. WC1H 0AJ. E-mail: f.d.king@ucl.ac.uk, a.e.aliev@ucl.ac.uk
† Electronic supplementary information (ESI) available: 1H NMR and
13C NMR for all compounds. CCDC reference numbers 787503. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00559b
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However, running the spectra at 60 ◦C improved the resolution, as
the exchange of conformers becomes fast in the NMR time scale at
higher temperatures. Interestingly, the presence of a substituent at
the C-15 position also reduced conformational freedom and sharp
spectra were obtained at ambient temperatures. We were able to
obtain sufficiently good crystals of 2f for an X-ray crystallographic
determination which confirmed the structure (Fig. 1).
The reduction/cyclisation also worked well for the synthesis of
10-substituted analogues. Thus, the 4-methyl-4-phenylbutyl imide
9 was reduced and cyclised to give the ‘trans’ 10 and ‘cis’ 11 isomers,
readily separable by column chromatography, in a ratio of 5.5 : 1
with an overall yield of 90% (Scheme 3).
Scheme 3 Synthesis of benzazocinones 10 and 11. Reagents and condi-
tions: a) NaBH4, KHCO3, b) CF3SO3H, CHCl3, heat.
Similarly, reduction and cyclisation of the 4,4-diphenylbutyl
imide 12 gave a mixture of the ‘trans’ 13 and the ‘cis’ 14 isomers in
an overall yield of 70%, although this time they were inseparable by
column chromatography (Scheme 4). However, the major ‘trans’
isomer was isolated from the mixture by crystallization from
EtOAc/petrol.
Fig. 1 Structure of 2f from X-ray structure analysis: CCDC 787503.†
This endocyclic acyliminium ion cyclisation can be readily
applied to the synthesis of products not readily achievable by
the exocyclic acyliminium ion methodology.2 Thus, whereas cy-
clisation of the 6-membered exocyclic N-acyliminium ion failed,2
reduction and cyclisation of the imide 3 readily gave the piperidino-
benzazocine 4 in 74% yield.
Scheme 4 Synthesis of benzazocinones ( )13 and ( )14 and ( )15 and
( )16. Reagents and conditions: a) NaBH4, KHCO3, b) CF3SO3H, CHCl3,
heat, then c) LiAlH4.
For the phthalimide 5,7 reduction and cyclisation gave the cyclic
product 6 (73% yield). With 5, we found that low temperatures and
buffering of the NaBH4 to avoid ring opening was not necessary.
The NMR of 6 at room temperature was poorly resolved. However,
on cooling to -60 ◦C, two distinct conformers were observed in a
ratio of 2.4 : 1, whereas heating to 125 ◦C gave a simplified time-
averaged spectrum. Although reduction and acid-mediated intra-
molecular cyclisations of N-arylethyl-homo-phthalimides onto
indole and phenyls to give 6-membered rings has been reported,8
the reduction and cyclisation of the homophthalimide 7 did
not give 8a, but instead gave the isoquinolone 8b (95% yield).8b
Prolonged heating of 8b with triflic acid failed to convert it into
8a.
An NMR study confirmed that the 10-phenyl group was
orientated ‘trans’ with respect to the pyrrolidinone ring. The ‘trans’
isomer has also been reported to be the major isomer obtained
from the equivalent exocyclic acyliminium ion cyclisation.2
Reduction of the mother liquors from the crystallization (which
contained a mixture of 13 and 14) with LiAlH4 gave the amines
15 and 16 in an overall yield of 95%. Similar reduction of 13 with
LiAlH4 gave only 15. The amines 15 and 16 were readily separable
by column chromatography on silica. Surprisingly, 15 was non-
polar (rf 0.7 on SiO2, elution with DCM) and rapidly eluted from
a SiO2 column with DCM, whereas 16 required the addition of 10%
MeOH and 1% 0.88 aqueous ammonia solution. Amine 15 rapidly
degraded on exposure to air.9 An aqueous ethanolic solution of
15 was found to have a neutral pH, but it was possible to form a
solid HCl salt, which was more stable.
A strong nuclear Overhauser effect (NOE) between 2-H and
10-H protons was observed in 16, showing that they are on
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the same side of the 8-membered ring, whereas no such NOE
was observed for 15. In 15, NOEs were observed between
the 3t-H (t = trans to 2-H) and 10-H protons. These NOEs
confirm the trans-configuration of the two methine protons 2-H
and 10-H in 15 and their cis-configuration in 16. Furthermore,
the same amine 15 was formed by LiAlH4 reduction of our
previously reported 10-phenylbenzazocin-7-one 17, for which we
had structural confirmation from X-ray analysis.2
cyclisation of the exocyclic pyrrolidinium ion onto phenyl gave a
1 : 2 ratio of the 8 : 6 membered cyclisation.2
The NMR analysis of the HCl salt of 15 showed that it exists
as a mixture of two forms, the ‘trans’ form 15a and the ‘cis’ form
15b, in a ratio of 15a : 15b = 57 : 43. The more polar amine 16 also
readily formed a solid HCl salt and NMR analysis showed that
this also existed as a mixture of the ‘cis’ 16a and ‘trans’ 16b ring
junction, but now the ‘cis’ form was the major form, with a ratio
of 16a : 16b = 62 : 38 (Fig. 2).
In order to determine whether these contrasting results were
due either to the position of the acyl group, or to the structural
differences between phthalimide and pyrrolidinone, we carried
out the reduction/cyclisation of 24. This led to the exclusive
formation of the isoquinolinone 25 (78% yield), with none of the
dibenzazocinone 26 detected (Scheme 6). Thus, in the absence of
strongly electron donating groups, reduction/cyclisation of both
the phthalimide and pyrrolidinone form the 6-membered ring
exclusively.
Scheme 6 Synthesis of the isoquinolone 25. Reagents and conditions: a)
NaBH4, b) CF3SO3H, CHCl3, heat.
Conclusion
Fig. 2 The structures of the major (15a) and minor (15b) forms of the
hydrochloride of 15 and the major (16a) and minor (16b) forms of the
hydrochloride of 16 in CDCl3 solution.
In conclusion, we have shown that the benzo-fused 8-membered
benzazocinones and dibenzazocinones can be readily prepared
in good yield by triflic acid-mediated endo-cyclic iminium ion
cyclisation. This method offers an alternative to our previously
reported exo-cyclic iminium ion cyclisation and allows the syn-
thesis of analogues not readily available by that route. We have
also identified a conformationally restricted tertiary amine that is
unusually non-polar.
We were also interested in investigating the use of this method-
ology in the synthesis of dibenzazocinones as conformationally
restricted analogues. It was found that both the 2-(2-benzyl) benzyl
imide 18 and the 2-(2-phenoxy) benzyl imide 19 reduced and
cyclised to give the 8-membered ring compounds 20 (95% yield)
and 21 (86% yield), respectively (Scheme 5).
Experimental
All reagents were commercially available, unless otherwise spec-
ified, and used without purification. The chloroform used was
stabilised with amylene. All non-crystalline final compounds were
found to be >95% pure by HPLC, and all crystalline compounds
>98% pure. Infrared spectra were run neat on a Perkin Elmer
100 FT IR spectrometer. Solution 1H and 13C NMR spectra
were recorded on Bruker NMR spectrometers AMX300, Avance
III 400, DRX500 and Avance III 600 equipped with z-gradient
facilities. 1H and 13C chemical shifts are given relative to TMS. Un-
less otherwise specified, spectra were recorded at 25 ◦C. Both
NOE and ROE measurements were undertaken for establishing
spatial proximities of protons. The latest implementations of
the corresponding 2D NMR experiments—NOESY with the
elimination of zero-quantum interference and EASY-ROESY—
were used, which offer considerably improved selectivity for NOE
Scheme 5 Synthesis of di-benzazocinones 20 and 21. Reagents and
conditions: a) NaBH4, b) CF3SO3H, CHCl3, heat.
The formation of 8-membered rings by reduction/cyclisation
of phthalimides has previously been reported only for the highly
electron rich phenyl 22, with 6-membered cyclisation occurring
without the activation of the 2-phenyl with electron donating
substituents 23.10 In contrast, we have previously reported that the
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and ROE measurements with minimum interference from other
sources.11
reflux for 1 h. On cooling to room temperature, water (50 ml) was
added and the product extracted into 4 : 1 Et2O–DCM (3 ¥ 100 ml).
The combined organic extracts were dried (K2CO3), concentrated
and trituration with petrol afforded the title compound 1a as a
beige solid 2.4 g (78% yield), mpt 46–48 ◦C (EtOAc/petrol); FT-
IR (neat) 3307, 2946, 1736, 1673, 1641, 1562, 1435, 1339, 1155,
1137, 743, 711, 702, 696 cm-1. HRMS theoretical mass: 231.12538;
General procedure for the preparation of the N-substituted imides
A stirred solution of the appropriate alcohol (10 mmol), triphenyl
phosphine (11 mmol) and the dried NH-imide (11 mol) was
dissolved in DCM (50 ml), cooled to 0 ◦C and treated with DEAD
(11 mmol) until a yellow colour remained. The reaction mixture
was left overnight at ambient temperature, the solvent removed
and the residue purified by column chromatography on SiO2,
eluting with DCM.
1
measured mass: 231.12579. H NMR (300 MHz, CDCl3): d =
1.54–1.67 (4H, m), 2.53–2.70 (6H, m, including 2.87, 4H, s), 3.45–
3.55 (2H, m), 7.10–7.30 (5H, m): 13C NMR and DEPT (75 MHz,
CDCl3) d = 27.3 (CH2), 28.2 (CH2), 28.6 (CH2), 35.3 (CH2), 38.6
(CH2), 125.8 (CH), 128.3 (CH), 128.4 (CH), 141.9 (C), 177.2 (C).
General procedure for the reduction of the N-substituted
succinimides to the hydroxy-amides using NaBH4
6-Aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-trien-5-one (2a)
The title compound was prepared as described in the general
procedures. 1a was reduced with NaBH4 to give the 5-hydroxy-
1-(4-phenyl-butyl)-pyrrolidin-2-one in an 80% yield as an oil. 1H
NMR (500 MHz, CDCl3): d = 1.45–1.66 (4H, m), 1.87 (1H, dt, J =
11.6, 1.6 Hz), 2.19–2.31 (2H, m), 2.50 (1H, quintet, J = 10.2 Hz),
2.56–2.68 (2H, m), 3.08–3.17 (1H, m), 3.40–3.51 (1H, m), 4.18
(0.4H, brs), 4.31 (0.6H, brs), 4.14 (1H, brs), 7.10–7.20 (3H, m),
7.21–7.32 (2H, m); 13C NMR and DEPT (125 MHz, CDCl3) d =
27.4 (CH2), 28.3 (CH2), 28.8 (CH2), 29.1 (CH2), 35.6 (CH2), 39.7
(CH2), 83.2 (CH), 125.9 (CH), 128.4 (CH), 128.5 (CH), 142.2 (C),
175.0 (C). Cyclisation of 5-hydroxy-1-(4-phenyl-butyl)-pyrrolidin-
2-one with triflic acid as described in the general procedure, with
heating for 1 h, gave the title compound 2a as a white solid (78%
yield): mpt 72–4 ◦C (EtOAc/petrol). HRMS theoretical mass:
215.13047; measured mass: 215.13125. FT-IR (neat) 1672, 1410,
A stirred solution of the appropriate N-substituted succinimide
(5 mmol) was dissolved in EtOH (30 ml) and saturated aqueous
KHCO3 solution (3 ml) added together with H2O (2 ml). On
cooling to 0–5 ◦C, NaBH4 (25 mmol) was added and the reaction
stirred at that temperature for 2–4 h, until most of the succinimide
had been reduced by TLC. Water (150 ml) was then added and
the product extracted into DCM (3 ¥ 50 ml), dried (K2CO3),
concentrated and the residue purified by column chromatography
on SiO2, eluting with DCM and 2–4% MeOH to give the desired
products.
General procedure for the reduction of the N-substituted
phthalimides to the hydroxy-amides using NaBH4
To a stirred, ethanolic (40 ml) suspension of the phthalimide
(5 mmol) and water (4 ml) was added NaBH4 (25 mmol) at ambient
temperature and the reaction stirred at ambient temperature for
1 h until no starting material was observed by TLC. Water (150 ml)
was then added and the solid product collected and dried.
1
1357, ◦1310, 1259, 1238, 771 cm-1. H NMR (600 MHz, CDCl3)
at 60 C: d = 1.43–1.51 (1H, m), 1.63–1.71 (1H, brm), 1.73–1.80
(1H, m), 1.84–1.92 (1H, brm), 1.98–2.70 (1H, m), 2.38–2.43 (1H,
m), 2.47 (1H, dd, J = 8.9, 17.5 Hz), 2.49–2.56 (1H, m), 2.72 (1H,
ddd, J = 4.5, 6.6, 13.7 Hz), 3.05 (1H, ddd, J = 4.3, 10.0, 13.8 H),
3.10–3.16 (1H, brm), 3.60–3.69 (1H, brm), 4.80 (1H, t, J = 7.5 Hz),
7.11 (1H, dd, J = 1.5, 7.4 Hz), 7.16 (1H, dd, J = 1.4, 7.6 Hz), 7.21
(1H, dt, J = 1.6, 7.6 Hz), 7.25 (1H, dt, J = 1.6, 7.3 Hz). 13C NMR
and DEPT (150 MHz, CDCl3) d = 24.8 (8-C), 28.2 (3-C), 29.2
(9-C), 31.0 (4-C), 31.6 (10-C), 41.6 (7-C), 63.1 (2-C), 126.5 (CH),
127.3 (15-C), 128.2 (CH), 131.5 (12-C), 139.0 (11-C), 140.2 (1-C),
174.6 (5-C).
General procedure for the triflic acid-mediated cyclisation
A solution of the hydroxy-amide (5 mmol) in chloroform (10 ml)
was added over 10 min to a heated (65 ◦C), stirred mixture of
triflic acid (50 mmol) in chloroform (40 ml). The reaction was
heated under gentle reflux for a given period. On cooling to
ambient temperature, water (20 ml) was added and the aqueous
layer carefully basified with solid K2CO3 (vigorous effervescence).
The reaction mixture was transferred to a separating funnel and
the lower layer separated. The aqueous layer was extracted with
DCM (50 ml) and the combined organic extracts dried (K2CO3).
Filtration and evaporation in vacuo gave the crude products which
were separated by column chromatography on silica.
6-Aza-benzo[c]tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-trien-5-
one (6)
To a stirred suspension of 5 7 (0.9 g, 3.2 mmol) in ethanol (30 ml)
at ambient temperature was added NaBH4 (0.6 g, 16 mmol) and
water (3 ml), and the reaction mixture was stirred at ambient
temperatures until TLC shows no 5 (~1 h). Water (200 ml) was then
added and the solid hydroxyamide that precipitated was collected
and dried (0.83 g, 92% yield), mpt 114–5 ◦C. FT-IR (neat) 3314,
1683, 1671, 1468, 1450, 1421, 1044, 751, 704, 695 cm-1. 1H NMR
(500 MHz, CDCl3): d = 1.51–1.70 (4H, m), 2.61 (2H, t, J = 5.8 Hz),
3.20–3.28 (1H, m), 3.39–3.48 (1H, m), 3.56 (1H, d, J = 11.9 Hz),
5.67 (1H, d, J = 11.9 Hz), 7.11–7.17 (3H, m), 7.24 (2H, t, J =
7.5 Hz), 7.42 (1H, dt, J = 0.95, 7.4 Hz), 7.52–7.60 (3H, m); 13C
NMR and DEPT (125 MHz, CDCl3) d = 27.83 (CH2), 28.75 (CH2),
35.52 (CH2), 38.89 (CH2), 81.69 (CH), 123.25 (CH), 123.35 (CH),
1-(4-Phenyl-butyl)-pyrrolidine-2,5-dione (1a)
A stirred solution of 4-phenylbutyl-1-amine (2.4 ml, 15 mmol) and
succinic anhydride (1.5 g, 15 mmol) in CHCl3 (30 ml) was heated
unde◦r reflux for 30 min. The reaction mixture was then cooled
to 0 C and MeOH (20 ml), thionyl chloride (1.3 ml, 18 mmol)
then added and the reaction heated under reflux for 3 h. On
cooling, the reaction was concentrated under reduced pressure on
a rotary evaporator, and the residue dissolved in toluene (50 ml)
and again concentrated as before. The residue was dissolved in
toluene (50 ml) and treated with 0.5 g NaOBu-t and heated under
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125.87 (CH), 128.39 (CH), 128.48 (CH), 129.79 (CH), 131.55 (C),
132.20 (CH), 142.12 (C), 143.93 (C), 167.50 (C).
stirred solution of the hydroxyamide (0.89 g, 2.9 mmol) in CHCl3
(30 ml) was treated with triflic acid (2.9 ml) and heated under reflux
for 30 min. On cooling, water (10 ml) was added and the reaction
carefully basified by addition of solid K2CO3. The product was
extracted into DCM (3 ¥ 50 ml), dried (K2CO3), concentrated
in vacuo and the residue purified by column chromatography on
SiO2, eluting with DCM + 1% MeOH to give 8b as a white solid
(0.77 g, 95% yield), mpt 58–59 ◦C (ether/petrol). FT-IR (neat)
1641, 1623, 1598, 1491, 1373, 1296, 794, 750, 690 cm-1. Theoretical
mass: 277.14612; measured mass: 277.14557. 1H NMR (500 MHz,
CDCl3): d = 1.71 (2H, quintet, J = 7.3 Hz), 1.82 (2H, quintet,
J = 7.4 Hz), 2.66 (2H, t, J = 7.6 Hz), 4.01 (2H, t, J = 7.3 Hz),
6.47 (1H, d, J = 7.3 Hz), 7.02 (1H, d, J = 7.3 Hz), 7.14–7.20
(3H, m), 7.24–7.29 (2H, m), 7.46–7.52 (2H, m), 7.62 (1H, ddd,
J = 1.3, 7.1, 8.3 Hz), 8.43 (dd, J = 0.5, 8.1 Hz). 13C NMR and
DEPT (125 MHz, CDCl3) d = 28.66 (CH2), 28.99 (CH2), 35.64
(CH2), 49.30 (CH2), 106.05 (CH), 125.89 (CH), 125.92 (CH),
126.40 (C), 126.84 (CH), 127.92 (CH), 128.43 (CH), 128.50 (CH),
131.72 (CH), 132.10 (CH), 137.07 (C), 142.05 (C), 162.18 (C).
A solution of the hydroxyamide (0.44 g, 1.5 mmol) in CHCl3
(5 ml) was added to a stirred mixture of triflic acid (1.5 ml) in
CHCl3 (20 ml) and the reaction mixture heated under reflux for
2 h. On cooling, water was added (10 ml) and the aqueous layer
made basic by careful addition of solid K2CO3. The product was
extracted into DCM (3 ¥ 50 ml), dried (K2CO3), concentrated and
purified by column chromatography on SiO2, eluting with 1 : 1
petrol : DCM to give the title compound 6 as a white solid (0.30 g,
73% yield), mpt 150–152 ◦C. FT-IR (neat) 1683, 1465, 1407, 1365,
1315, 1301, 755, 743, 720, 688 cm-1. 1H NMR (400 MHz, CDCl3,
-60 ◦C): two conformations in a ratio of 2.4 : 1: d = 1.4–1.72 (2H,
m), 1.94–2.06 (0.29H, m), 2.15–2.43 (2H, m), 2.55–2.68 (0.29H,
m), 2.98–3.18 (1.14H, m), 3.36 (0.29H, d, J = 14.0 Hz), 4.48 (0.71H,
dd, J = 9.5, 13.9 Hz), 4.57 (0.29H, ddd, J = 5.1, 12.3, 13.9 Hz), 5.63
(0.29H, s), 5.94 (0.71H, s), 6.55 (0.71H, d, J = 7.8 Hz), 7.01 (0.29H,
d, J = 7.4 Hz), 7.06–7.16 (0.71H, m), 7.22 (0.29H, d, J = 7.2 Hz),
7.25–7.67 (5H, m), 7.87 (0.29H, d, J = 7.5 Hz), 7.94 (0.71H, d, J =
7.4 Hz). 13C NMR (100 MHz, CDCl3, -60 ◦C) d = 22.4, 26.9, 28.7,
30.5, 31.8, 34.2, 39.1, 42.0, 122.9, 123.4, 123.7, 123.8, 126.8, 127.4,
127.6, 128.5, 128.7, 129.6, 130.2, 130.9, 131.9, 132.2, 133.5, 134.0,
2-(4,4-Diphenyl-butyl)-pyrrolidine-2,5-dione (12)
1
135.9, 138.7, 143.3, 144.4, 144.8. H NMR (400 MHz, CDCl3,
A stirred solution of 4,4-diphenylbutan-1-ol13 (2.4 g, 11 mmol),
triphenylphosphine (2.9 g, 12 mmol) and dried succinimide (1.1 g,
12 mmol) in DCM (50 ml) was cooled to 0 ◦C and DEAD
(1.8 ml, 12 mmol) was added dropwise. The reaction mixture was
stirred at ambient temperatures overnight and then concentrated
in vacuo. The residue was purified by column chromatography
on SiO2, eluting with 2 : 3 petrol : DCM to 1 : 4 petrol : DCM to
give the title product as a white solid (3.2 g, 84% yield), mpt 91–
93 ◦C (Et2O/petrol); theoretical mass: 307.15668; measured mass:
307.15655. 1H NMR (500 MHz, CDCl3): d = 1.20–1.56 (2H, m),
2.03 (2H, q, J = 7.9 Hz), 2.65 (4H, s), 3.52 (2H, t, J = 7.3 Hz),
3.90 (1H, t, J = 7.9 Hz), 7.15–7.28 (10H, m); 13C NMR (125 MHz,
CDCl3): d = 26.3 (CH2), 28.2 (CH2), 32.8 (CH2), 38.7 (CH2), 51.0
(CH), 126.2 (CH), 127.9 (CH), 128.6 (CH), 144.6 (C), 177.3 (C)
◦
125 C): d = 1.52–1.90 (4H, m), 2.68–2.87 (2H, m), 3.56 (H-8, t,
J = 11.5 Hz), 3.68 (H-8, dt, J = 3.2, 11.2 Hz), 5.93 (H-14b, s), 7.08
(H-1, d, J = 7.4 Hz), 7.16 (H-4, dd, J = 1.4, 7.4 Hz), 7.24 (H-2, dt,
J = 1.6, 7.4 Hz), 7.30 (H-3, dt, J = 1.4, 7.4 Hz), 7.33 (H-14, d, J =
7.6 Hz), 7.40 (H-12, dt, J = 1.3, 7.4 Hz), 7.57 (H-13, t, J = 7.4 Hz),
7.75 (H-11, d, J = 7.4 Hz)
2-(4-Phenyl-butyl)-4H-isoquinoline-1,3-dione (7)12
A solution of 4-phenylbutyl-1-amine (1.6 g, 11 mmol) (10 ml) and
homophthalic anhydride (1.8 g, 11 mmol) in CHCl3 was stirred
at ambient temperature for 5 min, then heated to 200 ◦C (heating
block temperature), driving off the CHCl3 and H2O for 30 min.
The reaction mixture was cooled and the residue dissolved in
DCM (5 ml) and purified by column chromatography on SiO2,
eluting with DCM to give 7, 2.8 g (87% yield), as a white solid,
recrystallized from EtOAc/petrol, mpt 84–86 ◦C. Theoretical
mass: 291.14103; measured mass: 291.14156. 1H NMR (500 MHz,
CDCl3): d = 1.64–1.75 (4H, m), 2.66 (2H, t, J = 6.8 Hz), 3.99–4.06
(4H, m), 7.12–7.18 (3H, m), 7.20–7.28 (3H, m), 7.44 (1H, t, J =
7.8 Hz), 7.58 (1H, t, J = 7.5 Hz), 8.20 (1H, d, J = 8.0 Hz): 13C
NMR and DEPT (125 MHz, CDCl3) d = 27.8 (CH2), 29.0 (CH2),
35.7 (CH2), 36.5 (CH2), 40.1 (CH2), 125.5 (C), 125.8 (CH), 127.2
(CH), 127.8 (CH), 128.4 (CH), 128.5 (CH), 129.2 (CH), 133.6
(CH), 134.2 (C), 142.3 (C), 164.9 (C), 170.0 (C).
(2R,10R; 2S,10S)-10-Phenyl-6-aza-tricyclo[9.4.0.0*2,6*]-
pentadeca-1(11),12,14-trien-5-one (13) and (2R,10S; 2S,10R)-
10-phenyl-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-5-one (14)
A stirred suspension of 12 (2.0 g, 6.6 mmol) in ethanol (90 ml)
was cooled to 5 ◦C and NaBH4 (1.0 g, 27 mmol) was added
followed by saturated aqueous KHCO3 (9 ml) and the reaction
was stirred at 5 ◦C for 4 h. Water (300 ml) was then added and the
product extracted into CHCl3 (3 ¥ 100 ml). The combined organic
extracts were dried (K2CO3), concentrated and purified by column
chromatography, eluting with ether to give recovered 12 (0.13 g,
20% yield) and the hydroxyamide (1.32 g, 65% yield) as an oil. 1H
NMR (500 MHz, CDCl3): d = 1.40–1.55 (2H, m), 1.80–1.89 (1H,
m), 1.94–2.02 (2H, m), 2.10–2.21 (2H, m), 2,44–2.52 (2H, m), 3.12
(2H, tt, J = 5.9, 7.6 Hz), 3.47 (2H dt, J = 7.8, 13.6 Hz), 3.86 (2H,
t, J = 8.1 Hz), 5.08 (1H, dd, J = 2.6, 6.3 Hz), 7.09–7.28 (10H, m);
13C NMR (125 MHz, CDCl3): d = 26.2 (CH2), 28.3 (CH2), 29.0
(CH2), 32.9 (CH2), 39.7 (CH2), 51.1 (CH), 83.1 (CH), 126.3 (CH),
127.9 (CH), 128.6 (CH), 144.8 (C), 174.9 (C).
2-(4-Phenyl-butyl)-2H-isoquinolin-1-one (8b)
A stirred solution of 7 (1.9 g, 6.5 mmol) in EtOH (50 ml) was
cooled to 5 ◦C and treated with NaBH4 (1.2 g, 0.32 mmol),
saturated KHCO3 solution (3 ml) and water (5 ml), and cooling
and stirring was continued for 3 h. Water (200 ml) was added
and the solid collected, dissolved in DCM and purified by column
chromatography on SiO2, eluting with 1 : 5 ether : DCM to give the
hydroxyamide as a white solid (1.47 g, 77% yield) that started to
go yellow on standing with formation of the title compound 8b. A
A solution of the hydroxyamide (1.32 g, 4.2 mmol) in CHCl3
(15 ml) was added, dropwise, to a stirred mixture of triflic acid
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(4.2 ml, 45 mmol) in CHCl3 (60 ml) at 65 ◦C over 5 min. The reac-
tion was heated under reflux for 1 h, cooled to r.t., then water was
added (20 ml) and the aqueous layer made basic by careful addition
of solid K2CO3. The product was extracted into DCM (3 ¥ 100 ml),
dried (K2CO3), concentrated and purified by column chromatog-
raphy on SiO2, eluting with Et2O/1% MeOH to give a 9 : 1 mixture
of 13 and 14 (0.93 g, 77% yield), from which pure 13 was obtained
by crystallization from Et2O (0.45 g, 37% yield), mpt 152–3 ◦C
(DMSO/water). FT-IR (neat) 1669, 1488, 1445, 1414, 1358, 1273,
1153, 762, 747, 697 cm-1. Theoretical mass: 291.16177; measured
mass: 291.16051. 1H NMR (500 MHz, CDCl3): d = 1.4–1.55 (m,
1H), 1.7–1.8 (m, 1H), 1.89–2.0 (m, 1H), 2.10 (dt, J = 2.5, 9.5 Hz,
1H), 2.22–2.32 (m, 1H), 2.43–2.62 (m, 3H), 3.02 (d, J = 13.5 Hz,
1H), 4.24 (brs, 1H), 4.80 (dd, J = 7.4, 8.9 Hz, 1H), 5.01 (dd, J =
4.6, 11.6 Hz, 1H), 6.76 (dd, 1H, J = 1.9, 7.5 Hz, 1H), 7.08–7.37 (m,
8H); 13C NMR and DEPT (125 MHz, CDCl3) d = 23.4 (CH2), 30.5
(CH2), 31.3 (CH2), 32.7 (CH2), 42.3 (CH2), 42.6 (CH), 65.8 (CH),
126.2 (CH), 126.4 (CH), 127.8 (CH), 128.4 (CH), 128.4 (CH),
128.5 (CH), 129.8 (CH), 139.6 (C), 142.9 (C), 144.1 (C), 175.2 (C).
(1H, t, J = 7.5 Hz, 2-H), 4.80 (1H, dd, J = 11.9, 3.5 Hz, 10-H), 6.47
(1H, dd, J = 12.0, 5.5 Hz, 10-H), 6.74 (1H, dd, J = 7.9, 1.5 Hz,
12-H), 7.10 (1H, td, J = 7.6, 1.5 Hz, 13-H), 7.20 (1H, td, J = 7.4,
1.5 Hz, 14-H), 7.25 (1H, m, p-H 10-Ph), 7.33 (2H, m, o-H 10-Ph),
7.35 (2H, m, m-H 10-Ph), 7.41 (1H, dd, J = 7.9, 1.5 Hz, 15-H); 13
C
NMR (150 MHz, CDCl3) at 25 ◦C: d = 23.1 (C4), 25.3 (C8), 30.9
(C3), 35.9 (C9), 42.7 (C10), 52.8 (C7), 55.5 (C5), 60.7 (C2), 125.9
(C15), 126.3 (Cp of 10-Ph), 126.3 (C14), 127.8 (C13), 127.8 (C12),
128.4 (Co of 10-Ph), 128.8 (Cm of 10-Ph), 138.1 (C1), 145.2 (C11),
145.4 (Cq of 10-Ph).
15 appeared to have limited stability in air and therefore both 15
and 16 were converted to their HCl salts by treatment of an ethereal
solution of the amines with an excess of ethereal HCl to give the
hydrochlorides 15a/15b and 16a/16b, respectively. 15a/15b: mpt
188–90 ◦C. FT-IR 2417 (br), 1452, 1424, 1031, 770, 749, 721, 703,
1
667 cm-1. 15a H NMR (in a mixture with 15b, ratio 15a : 15b =
57 : 43, 600 MHz, CDCl3, 60 ◦C): d = 1.65 (1H, m, 4c-H (c = cis to
2-H)), 1.77 (1H, m, 3c-H), 1.95 (1H, m, 8t-H (t = trans to 2-H)),
1.97 (1H, m, 8c-H), 2.01 (1H, m, 9t-H), 2.30 (1H, m, 4t-H), 2.62
(1H, m, 3t-H), 2.70 (1H, m, 5c-H), 2.84 (1H, m, 7t-H), 2.97 (1H,
m, 9c-H), 3.15 (1H, br dd, J = 14.1, 7.5 Hz, 7c-H), 3.69 (1H, m,
5t-H), 3.87 (1H, ddd, J = 11.8, 10.4, 6.6 Hz, 2-H), 4.46 (1H, t, J =
4.5 Hz, 10-H), 7.08 (2H, m, o-H 10-Ph), 7.23 (1H, m, p-H 10-Ph),
7.28 (1H, br d, J = 7.6 Hz, 12-H), 7.31 (2H, m, m-H 10-Ph), 7.42
(1H, br t, J = 7.6 Hz, 13-H), 7.49 (1H, br t, J = 7.6 Hz, 14-H),
8.07 (1H, br d, J = 7.6 Hz, 15-H), 12.39 (1H, br s, 6-H). 13C NMR
(150 MHz, CDCl3, 60 ◦C): d = 16.8 (C8), 20.6 (C4), 27.3 (C3), 33.5
(C9), 48.6 (C7), 48.7 (C10), 51.1 (C5), 62.2 (C2), 126.3 (Co of 10-
Ph), 126.8 (Cp of 10-Ph), 128.9 (C14), 129.1 (Cm of 10-Ph), 129.2
(C1), 130.5 (C15), 131.0 (C13), 132.2 (C12), 141.7 (Cq of 10-Ph),
144.1 (C11). 15b 1H NMR (in a mixture with 15a, ratio 15a:15b =
4 : 3, 600 MHz, CDCl3, 60 ◦C): d = 2.00 (1H, m, 8t-H (t = trans to
2-H)), 2.15 (1H, m, 9t-H), 2.17 (1H, m, 7t-H), 2.21 (1H, m, 4t-H
(c = cis to 2-H)), 2.36 (1H, m, 3t-H), 2.46 (1H, m, 4c-H), 2.63 (1H,
m, 3c-H), 2.64 (1H, m, 5t-H), 2.67 (1H, m, 8c-H), 2.90 (1H, m,
9c-H), 3.20 (1H, br d, J = 13.2 Hz, 7c-H), 3.51 (1H, m, 5c-H), 4.42
(1H, dd, J = 8.5, 5.4 Hz, 10-H), 5.22 (1H, br dd, J = 7.8, 4.5 Hz,
2-H), 7.04 (2H, m, o-H 10-Ph), 7.18 (1H, m, p-H 10-Ph), 7.24 (1H,
br d, J = 7.2 Hz, 15-H), 7.26 (2H, m, m-H 10-Ph), 7.35 (1H, br d,
J = 7.2, 12-H), 7.38 (1H, td, J = 7.3, 1.5 Hz, 14-H), 7.40 (1H, br
t, J = 7.3 Hz, 13-H), 12.72 (1H, br s, 6-H); 13C NMR (150 MHz,
CDCl3, 60 ◦C): d = 22.9 (C8), 21.7 (C4), 27.6 (C3), 33.0 (C9), 48.2
(C7), 51.0 (C10), 51.5 (C5), 60.6 (C2), 126.7 (Co of 10-Ph), 126.9
(Cp of 10-Ph), 128.1 (C14), 128.6 (C15), 129.2 (Cm of 10-Ph), 130.6
(C13), 131.3 (C1), 133.5 (C12), 142.7 (Cq of 10-Ph), 145.3 (C11).
16a/16b: mpt = 144–146 ◦C (phase change) 196–198 ◦C, FT-
IR 2927, 2513 (br), 1495. 1447, 1410, 741, 698, 661 cm-1. 16a 1H
NMR (in a mixture with 16b, ratio 16a : 16b = 62 : 38, 600 MHz,
CDCl3, 60 ◦C): d = 1.83 (1H, tdd, J = 13.4, 11.7, 3.6 Hz, 9t-H
(t = trans to 2-H)), 1.95 (1H, dt, J = 13.3, 9.0 Hz, 7t-H), 2.24
(1H, m, 8t-H), 2.35 (1H, m, 4t-H), 2.52 (1H, m, 9c-H (c = cis to
2-H)), 2.54 (1H, m, 3t-H), 2.62 (1H, m, 8c-H), 2.63 (1H, m, 4c-H),
2.76 (1H, m, 5t-H), 3.08 (1H, m, 3c-H), 3.28 (1H, ddd, J = 13.3,
9.5, 1.8 Hz, 7c-H), 3.54 (1H, m, 5c-H), 4.53 (1H, dd, J = 11.7,
0.9 Hz, 10-H), 5.62 (1H, dd, J = 8.3, 4.5 Hz, 2-H), 6.94 (1H, m,
12-H), 7.22 (1H, m, 15-H), 7.22 (2H, m, o-H 10-Ph), 7.26 (1H, m,
13-H), 7.26 (1H, m, p-H 10-Ph), 7.27 (1H, m, 14-H), 7.34 (2H, m,
m-H 10-Ph), 12.98 (1H, br s, 6-H); 13C NMR (150 MHz, CDCl3,
60 ◦C): d = 22.1 (C4), 25.3 (C8), 28.4 (C3), 35.5 (C9), 45.8 (C10),
(2R,10R; 2S,10S)-10-Phenyl-6-aza-tricyclo[9.4.0.0*2,6*]-
pentadeca-1(11),12,14-trienene (15) and (2R,10S; 2S,10R)-10-
phenyl-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-trienene
(16)
The mother liquors from the crystallization of 13 (0.48 g,
1.6 mmol) was dissolved in dry THF (20 ml) with stirring under
argon and a 1 M solution of LiAlH4 in THF (1.0 ml, 1 mmol) was
added and the reaction heated under reflux for 1 h. The reaction
mixture was then cooled, Et2O (50 ml) added, followed by careful
addition of 2 M NaOH (0.3 ml). The reaction was stirred for
30 min, filtered through celite and the celite and aluminium salts
were washed thoroughly with DCM (2 ¥ 50 ml). The combined
organics were concentrated in vacuo, and the residue purified by
column chromatography in SiO2, eluting with DCM to give 15 as
an oil (0.35 g, 78% yield), then DCM + 10% MeOH + 1% 0.88
ammonia to give 16 as an oil (0.075 g, 17% yield). 15: theoretical
mass: 277.18250; measured mass: 277.18159. 1H NMR (600 MHz,
CDCl3, 60 ◦C): d = 1.50 (1H, m, 8c-H (c = cis to 2-H)), 1.56 (1H,
m, 8t-H (t = trans to 2-H)), 1.77 (1H, m, 4c-H), 1.91 (1H, m, 3t-H),
1.92 (1H, m, 4t-H), 1.94 (1H, m, 9t-H), 2.14 (1H, tdd, J 12.7, 3.7
and 5.4, 9c-H), 2.22 (1H, m, 5c-H), 2.23 (1H, m, 3c-H), 2.55 (1H,
m, 7c-H), 3.04 (1H, ddd, J = 13.2, 12.0, 5.2 Hz, 7t-H), 3.14 (1H,
m, 5t-H), 3.49 (1H, dd, J = 9.4, 7.4 Hz, 2-H), 6.47 (1H, dd, J =
12.0, 5.5 Hz, 10-H), 6.62 (1H, dd, J = 7.8, 1.5 Hz, 12-H), 7.00 (1H,
td, J = 7.5, 1.8 Hz, 13-H), 7.06 (1H, td, J = 7.6, 1.5 Hz, 14-H),
7.09 (1H, dd, J = 7.7, 1.8 Hz, 15-H), 7.22 (1H, m, p-H 10-Ph),
7.32 (2H, m, o-H 10-Ph), 7.33 (2H, m, m-H 10-Ph); 13C NMR
(150 MHz, CDCl3) at 60 ◦C: d = 22.2 (C4), 24.4 (C8), 33.1 (C9),
37.4 (C3), 43.3 (C10), 55.7 (C7), 56.3 (C5), 71.1 (C2), 125.2 (C14),
125.7 (Cp of 10-Ph), 126.4 (C13), 127.4 (C15), 128.1 (Cm of 10-Ph),
128.9 (Co of 10-Ph), 129.1 (C12), 142.2 (C11), 142.7 (C1), 145.5
(Cq of 10-Ph). 16: theoretical mass: 277.18250; measured mass:
277.18147. 1H NMR (600 MHz, CDCl3, 25 ◦C): d = 1.38 (1H, m,
8t-H (c = cis to 2-H)), 1.86 (1H, m, 8c-H (t = trans to 2-H)), 1.90
(1H, m, 9t-H), 2.02 (1H, m, 4c-H), 2.11 (1H, m, 4t-H), 2.25 (1H,
m, 9c-H), 2.32 (1H, dddd, J = 13.1, 10.0, 7.9, 6.3 Hz, 3c-H), 2.43
(1H, dddd, J = 13.1, 10.3, 6.1, 5.2 Hz, 3t-H), 2.67 (1H, m, 5c-H),
2.67 (2H, m, 7-H), 3.01 (1H, ddd, J = 9.5, 8.1, 4.4 Hz, 5t-H), 4.35
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48.6 (C7), 51.2 (C5), 59.2 (C2), 126.8 (Cp of 10-Ph), 127.0 (C15),
127.0 (C14), 128.4 (Co of 10-Ph), 128.7 (Cm of 10-Ph), 129.3 (C12),
129.8 (C1), 130.7 (C13), 144.4 (Cq of 10-Ph), 147.5 (C11). 16b 1H
NMR (in a mixture with 16a, ratio 16a : 16b = 62 : 38, 600 MHz,
CDCl3, 60 ◦C): d = 1.65 (1H, m, 8t-H (t = trans to 2-H)), 1.98 (1H,
m, 9t-H), 2.00 (1H, m, 8c-H (c = cis to 2-H)), 2.20 (1H, m, 4c-H),
2.24 (1H, m, 9c-H), 2.42 (1H, m, 3c-H), 2.49 (1H, m, 4t-H), 3.01
(1H, m, 5t-H), 3.05 (1H, m, 7c-H), 3.08 (1H, m, 3t-H), 3.53 (1H,
dt, m, 7t-H), 4.13 (1H, m, 5c-H), 4.58 (1H, dd, J = 12.3, 4.0 Hz,
10-H), 4.79 (1H, ddd, J = 11.5, 9.5, 6.3 Hz, 2-H), 6.78 (1H, dd, J =
7.9, 1.4 Hz, 12-H), 7.26 (1H, m, 13-H), 7.26 (1H, m, p-H 10-Ph),
7.29 (2H, m, o-H 10-Ph), 7.33 (1H, m, 14-H), 7.36 (2H, m, m-H
10-Ph), 7.89 (1H, dd, J = 8.0, 1.4◦Hz, 15-H), 12.46 (1H, br s, 6-H);
13C NMR (150 MHz, CDCl3, 60 C): d = 21.5 (C4), 21.7 (C8), 29.7
(C3), 34.8 (C9), 42.8 (C10), 53.2 (C7), 55.4 (C5), 64.9 (C2), 127.0
(Cp of 10-Ph), 127.5 (C14), 128.0 (C15), 128.2 (C12), 128.5 (Co of
10-Ph), 128.6 (Cm of 10-Ph), 129.2 (C1), 130.7 (C13), 143.0 (C11),
144.7 (Cq of 10-Ph).
(CH), 123.9 (CH), 127.2 (CH), 127.2 (CH), 127.5 (CH), 128.5
(CH), 128.7 (CH), 129.4 (CH), 129.8 (CH), 131.1 (CH), 131.4 (C),
132.1 (CH), 132.4 (CH), 133.6 (C), 134.6 (C), 137.2 (C), 137.3 (C),
145.0 (C), 168.5 (C).
6-Aza-10-oxa-dibenzo[c,f]tricyclo[9.4.0.0*2,6*]pentadeca-
1(11),12,14-trien-5-one (21)
2-Phenoxy-phenyl-methanol15 (1.5 g, 7.5 mmol) was converted
to the imide 19 by the previously described general procedure
but with the product 19 being purified on SiO2, eluting with
3 : 1 petrol : DCM and isolated as a white solid from ether/petrol
(1.6 g, 65% yield), mpt 91–93 ◦C. FT-IR (neat) 1703, 1484, 1428,
1391, 1349, 1330, 1235, 1076, 935, 751, 711, 689 cm-1. Theoretical
mass: 329.10464; measured mass: 329.10354. 1H NMR (500 MHz,
CDCl3): d = 4.97 (2H, s), 6.88 (1H, dd, J = 0.8, 8.1 Hz), 6.95 (2H,
dd, J = 0.9, 7.7 Hz), 7.00 (1H, t, J = 7.4 Hz), 7.09 (1H, dt, J = 0.9,
7.5 Hz), 7.20–7.29 (3H, m), 7.32 (1H, dd, J = 1.1, 7.6 Hz), 7.66–
7.70 (2H, m), 7.78–7.82 (2H, m). 13C NMR (125 MHz, CDCl3): d =
37.0 (CH2), 118.2 (CH), 119.3 (CH), 123.0 (CH), 123.3 (CH), 123.9
(CH), 127.5 (C), 129.1 (CH), 129.5 (CH), 129.7 (CH), 132.2 (C),
134.0 (CH), 154.4 (C), 157.4 (C), 168.0 (C). A solution of 19 (0.7 g,
2.1 mmol) was reduced to the hydroxyamide by the procedure
described for 7, extracting the product into CHCl3 (3 ¥ 50 ml),
drying and concentrating in vacuo (0.68 g, 96% yield), isolating as
an oil, and used without further purification. 1H NMR (500 MHz,
CDCl3): d = 3.85 (1H, d, J = 10.2 Hz), 4.67 (1H, d, J = 15.3 Hz),
4.79 (1H, d, J = 15.3 Hz), 5.72 (1H, d, J = 10.2 Hz), 6.87 (1H, dd,
J = 0.6, 8.2 Hz), 6.96 (2H, dd, J = 1.0, 8.7 Hz), 7.05 (1H, dt, J =
0.9, 7.4 Hz), 7.08 (1H, t, J = 7.4 Hz), 7.21 (1H, dt, J = 1.6, 8.0 Hz),
7.28–7.34 (3H, m), 7.38 (1H, dt, J = 0.7, 7.5 Hz), 7.50 (1H, dt, J =
6-Aza-dibenzo[c,f]tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-5-one (20)
2-Benzyl-phenyl-methanol14 (1.46 g, 7.3 mmol) was converted to
the imide 18 by the previously described general procedure, with 18
being purified on SiO2, eluting with 1 : 1 petrol : DCM and isolated
by crystallization from Et2O as a white solid, 1.8 g (75% yield),
mpt 130–133 ◦C. FT-IR (neat) 1768, 1697, 1421, 1390, 1358, 1331,
1108, 1073, 958, 939, 753, 736, 719, 709, 699 cm-1. Theoretical
mass: 327.12538; measured mass: 327.12450. 1H NMR (500 MHz,
CDCl3): d = 4.27 (2H, s), 4.80 (2H, s), 7.06–7.12 (3H, m), 7.15
(1H, dd, J = 1.7, 7.3 Hz), 7.17–7.25 (4H, m), 7.37 (1H, dd, J =
1.7, 7.1 Hz), 7.68 (2H, dd, J = 3.0, 5.5 Hz), 7.78 (2H, dd, J = 3.0,
5.5 Hz); 13C NMR (125 MHz, CDCl3): d = 38.8 (CH2), 39.3 (CH2),
123.3 (CH), 126.0 (CH), 126.9 (CH), 128.1 (CH), 128.5 (CH),
129.5 (CH), 131.0 (CH), 132.1 (C), 134.0 (CH), 138.4 (C), 140.5
(C), 168.2 (C). A solution of 18 (0.81 g, 2.5 mmol) was reduced
to the hydroxyamide by the procedure described for 7, extracting
the product into CHCl3 (3 ¥ 50 ml), drying and concentrating
in vacuo to give the hydroxyamide as a white solid (0.75 g, 93%
1.0, 7.4 Hz), 7.55 (1H, d, J = 7.5 Hz), 7.65 (1H, d, J = 7.5 Hz); 13
C
NMR (125 MHz, CDCl3): d = 37.6 (CH2), 81.5 (CH), 118.1 (CH),
119.2 (CH), 123.3 (CH), 123.5 (CH), 124.3 (CH), 129.2 (CH),
129.8 (CH), 129.9 (CH), 130.5 (C), 130.7 (CH), 131.4 (C), 132.3
(CH), 143.9 (C), 154.60 (C), 157.3 (C), 167.6 (C). A solution of the
hydroxyamide (0.66 g, 2 mmol) was cyclised following the general
procedure with 2 ml of triflic acid with heating at 50 ◦C for 15 min.
Purification was by column chromatography on SiO2, eluting with
DCM + 20% Et2O, and gave 21 as a white solid (0.57 g, 86% yield),
mpt 234–236 ◦C (CHCl3/petrol). FT-IR (neat) 1687, 1483, 1464,
1450, 1429, 1390, 1354, 1318, 1215, 811, 779, 761, 748, 737, 713,
686 cm-1. Theoretical mass: 313.10973; measured mass: 313.10919.
1H NMR (500 MHz, CDCl3): d = 4.53 (1H, d, J = 16.4 Hz), 4.92
(1H, d, J = 16.4 Hz), 5.80 (1H, s), 7.07–7.16 (m, 2H), 7.18–7.38
(m, 6H), 7.40 (1H, dd, J = 1.1, 7.5 Hz), 7.46 (1H, t, J = 7.3 Hz),
7.51 (1H, dt, J = 0.8, 7.3 Hz), 7.85 (1H, d, J = 7.4 Hz); 13C NMR
(125 MHz, CDCl3): d = 44.1 (CH2), 64.56 (CH), 122.5 (CH), 122.8
(CH), 123.8 (CH), 124.0 (CH), 124.9 (CH), 125.8 (CH), 128.2 (C),
128.6 (CH), 129.4 (C), 129.7 (CH), 130.2 (CH), 130.7 (CH), 131.8
(CH), 131.9 (C), 144.5 (C), 155.0 (C), 156.7 (C), 168.8 (C).
◦
1
yield), mpt 128–130 C. H NMR (500 MHz, CDCl3): d = 3.33
(1H, d, J = 11 Hz), 4.09 (1H, d, J = 16 Hz), 4.11 (1H, d, J = 16 Hz),
4.18 (1H, d, J = 15 Hz), 4.77 (1H, d, J = 15 Hz), 5.37 (1H, d, J =
11 Hz), 7.05–7.10 (3H, m), 7.14–7.28 (6H, m), 7.31–7.35 (1H, m),
7.44–7.49 (2H, m), 7.56 (1H, d, J = 7.5 Hz); 13C NMR (125 MHz,
CDCl3): d = 38.6 (CH2), 40.0 (CH2), 81.0 (CH), 123.3 (CH), 123.4
(CH), 126.1 (CH), 127.0 (CH), 128.1 (CH), 128.5 (CH), 128.8 (C),
129.7 (CH), 130.0 (CH), 131.2 (CH), 132.2 (CH), 134.9 (C), 140.5
(C), 143.8 (C), 167.1 (C). A solution of the hydroxyamide (0.65 g,
2 mmol) was cyclised following t◦he general procedure with 2 ml
of triflic acid with heating at 50 C for 15 min. Purification was
by column chromatography on SiO2, eluting with DCM + 20%
Et2O to give 20 as a white solid, mpt 220–222 ◦C (CHCl3/petrol).
FT-IR (neat) 1674, 1467, 1451, 1432, 1401, 1360, 1324, 773, 751,
734, 708, 688 cm-1. Theoretical mass: 311.13047; measured mass:
4-Phenyl-5,12b-dihydro-6H-isoindolo[1,2-a]isoquinolin-8-one (25)
2-Biphenylethan-2-ol16 was converted to the imide 24 by the
previously described general procedure, with 24 being purified
on SiO2, eluting with 1 : 1 petrol : DCM, and isolated as a white
solid (~100% yield), mpt 98–101 ◦C. FT-IR (neat) 1691, 1435,
1399, 1347, 1314, 1255, 1164, 1151, 1111, 921, 820, 761, 741, 716,
666 cm-1. Theoretical mass: 279.12538; measured mass: 279.12539.
1
311.12969. H NMR (500 MHz, CDCl3): d = 3.34 (1H, d, J =
14.3 Hz), 3.83 (1H, d, J = 14.3 Hz), 4.50 (1H, d, J = 16.6 Hz), 5.20
(1H, d, J = 16.6 Hz), 5.76 (1H, s), 7.11–7.21 (4H, m), 7.23–7.34
(4H, m), 7.45–7.55 (3H, m), 7.88 (1H, d, J = 7.5 Hz): 13C NMR
(125 MHz, CDCl3): d = 38.8 (CH2), 46.2 (CH2), 67.8 (CH), 122.9
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1H NMR (300 MHz, CDCl3): d = 2.56 (4H, s), 2.88 (2H, t, J =
7.5 Hz), 3.58 (2H, t, J = 7.5 Hz), 7.19–7.50 (9H, m); 13C NMR
(75 MHz, CDCl3): d = 28.0 (CH2), 30.8 (CH2), 39.5 (CH2), 126.7
(CH), 127.1 (CH), 127.4 (CH), 128.3 (CH), 129.2 (CH), 129.7
(CH), 130.4 (CH), 135.3 (C), 141.2 (C), 142.5 (C), 176.8 (C). The
imide 24 (0.8 g) was reduced with NaBH4 by the method described
in the general procedure to give the hydroxyamide, 0.43 g as an
oil, purified on SiO2, eluting with DCM + 2% MeOH (53% yield);
1H NMR (500 MHz, CDCl3): d = 1.70–1.78 (1H, m), 2.06–2.20
(2H, m), 2.34–2.44 (1H, m), 2.76–2.92 (2H, m), 3.09–3.18 (1H,
m), 3.24 (1H, d, J = 7.7 Hz), 3.44–3.52 (1H, m), 4.70 (1H, dt, J =
2.3, 7.7 Hz), 7.20–7.45 (9H, m); 13C NMR (125 MHz, CDCl3):
d = 28.1 (CH2), 28.9 (CH2), 31.2 (CH2), 40.9 (CH2), 83.3 (CH),
126.7 (CH), 127.2 (CH), 127.7 (CH), 128.3 (CH), 129.3 (CH),
129.9 (CH), 130.3 (CH), 136.2 (C), 141.7 (C), 142.2 (C), 174.7(C).
The amide (0.43 g) was cyclised with triflic acid (1.5 ml) following
the general procedure and the product purified on SiO2, eluting
with DCM + 1% MeOH to give 25, 0.33 g (80% yield) as an oil:
theoretical mass: 263.13047; measured mass: 262.12977. FT-IR
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1
(neat) 1676, 1462, 1416, 1363, 1316, 907, 760, 726, 702 cm-1. H
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Acknowledgements
The authors would like to thank Dr Lisa D. Haigh for the mass
spectra.
1554 | Org. Biomol. Chem., 2011, 9, 1547–1554
This journal is
The Royal Society of Chemistry 2011
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