A facile synthesis of pyrrolo-(di)-benzazocinones via an intramolecular N-acyliminium ion cyclisation

Article abstract of DOI:10.1039/b815195d

A facile, moderate to high yielding synthesis of hexahydro-(di)- benzazocinones is described via an intramolecular N-acyliminium ion cyclisation. The iminium ion intermediates are formed from the readily available 4,4-diethoxybutyl amides with an excess of triflic acid. For electron-withdrawing substituents, better yields were obtained from the pre-formed 2-hydroxypyrrolidine amides. From NMR studies, at ambient temperatures the pyrrolo-benzazocin-3-ones exist as a slowly equilibrating mixture of two conformations.

Full text of DOI:10.1039/b815195d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A facile synthesis of pyrrolo-(di)-benzazocinones via an intramolecular
N-acyliminium ion cyclisation†
Frank D. King,* Abil E. Aliev, Stephen Caddick, Derek A. Tocher and Denis Courtier-Murias
Received 1st September 2008, Accepted 10th October 2008
First published as an Advance Article on the web 12th November 2008
DOI: 10.1039/b815195d
A facile, moderate to high yielding synthesis of hexahydro-(di)-benzazocinones is described via an
intramolecular N-acyliminium ion cyclisation. The iminium ion intermediates are formed from the
readily available 4,4-diethoxybutyl amides with an excess of triflic acid. For electron-withdrawing
substituents, better yields were obtained from the pre-formed 2-hydroxypyrrolidine amides. From
NMR studies, at ambient temperatures the pyrrolo-benzazocin-3-ones exist as a slowly equilibrating
mixture of two conformations.
acid.15 On treatment of 1 with triflic acid (10 equivs.) in CHCl3
Introduction
we isolated the 6-membered cyclisation product 2 (64% yield) as
We have an on-going programme of work directed towards
expected (Scheme 1), but in addition a second, isomeric product.
1H and 13C NMR spectra provided evidence that the product was
the dibenzazocine 3 (29% yield). The key difference between the
13C NMR spectra of 2 and 3 were the number of aromatic carbon
signals, 10 signals for 2, 6 of which were C–H, and 12 signals for
3, 8 of which were C–H. The present observation is, as far as we
can ascertain, the first example of an acyliminium ion cyclisation
onto an unactivated aromatic to form an 8-membered ring.16,17
Although benzo-fused 7-membered rings have been extensively
exploited in drug discovery, for example tricyclic antidepressants,18
benzodiazepines19 and as enzyme inhibitors,20 there have only
been a few examples of pharmacologically active benzo-fused 8-
membered rings described in the literature.21–24 To date, hexahydro-
benzazocines have been prepared either by ring expansion,21,25–27
by ring-closing metathesis,28,29 and by intramolecular cyclisation
via either a Staudinger–aza-Wittig procedure22 or iminium ion
cyclisations of sulfonamides.30–33 We therefore believed that this
finding deserved further investigation.
Following the isolation of 3, we decided to investigate the
synthesis of the simpler hexahydro-benzazocinone 5 from 4-
phenylbutyramide 4 (Scheme 2), prepared in a similar manner
to 1 from 4-phenylbutyric acid. Cyclisation with triflic acid gave
a good yield (70%) of a colourless oil, tentatively assigned as
the hexahydrobenzazocinone 5 together with a small amount of 1-
tetralone (8% yield). The reaction was carried out at between 0.05–
0.1 M concentration demonstrating that no special procedures
(e.g. high dilution) were required to mediate this ring formation.
the development of new chemistry to allow the synthesis of
privileged structures for the assembly of high quality screening
libraries. We are interested in the synthesis of conformationally
restricted aryl-substituted alkylamines, privileged structures which
are found in CNS drugs,1–3 and particularly interested in 1,2,3,4-
tetrahydro-isoquinoline and its homologues, for which there have
been numerous reports on their biological activity.4–13 As an
example of a new synthesis of the 1,2,3,4-tetrahydro-isoquinoline
core, we recently described a synthesis of ( )-crispine A via an
intramolecular cyclisation of a readily synthesized N-acyliminium
ion.14 In this paper, we describe the unexpected isolation of
a pyrrolo-dibenzazocin-3-one (3) from a pyrrolo-isoquinolone
synthesis via an immimium ion cyclisation and the application
of this methodology to related systems.
Results and discussion
Whilst investigating the scope of this tetrahydro-isoquinoline
synthesis, we attempted the triflic acid-mediated cyclisation of
compound 1, which was readily prepared from biphenyl-2-acetic
Department of Chemistry, University College London, 20 Gordon Street,
London, WC1H 0AJ, U.K.. E-mail: f.d.king@ucl.ac.uk
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. CCDC reference numbers 690260, 703700 and 703701. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b815195d
Scheme 1 Synthesis of the tetrahydro-dibenzazocine 3. Reagents and conditions: a) (COCl)2, CH2Cl2, DMF, b) H2N(CH2)3CH(OEt)2, EtNMe2,
c) CF3SO3H, CHCl3, heat.
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In order to obtain a solid derivative to unambiguously confirm
the molecular structure, 5 was reduced to the amine with LAH and
a solid picrate salt 6 formed. Unfortunately good quality crystals
of the picrate could not be obtained. However, the structure of
this salt was confirmed by a low resolution X-ray crystal structure
analysis. In addition, the structure of the corresponding free base
was also confirmed by NMR measurements in CDCl3 (Fig. 2).
Scheme 2 Synthesis of benzazocines 5 and 6. Reagents and conditions:
a) (COCl)2, CH2Cl2, DMF, b) H2N(CH2)3CH(OEt)2, EtNMe2 (100%),
c) CF3SO3H, CHCl3, heat (70%), d) LiAlH4, THF, heat (88%), e) picric
acid.
Under these strongly acidic conditions, it is likely that the
acyliminium ion is protonated on the carbonyl to form the
dicationic superelectrophile, which undergoes the cyclisation.34
At ambient temperatures, the 1H and 13C NMR spectra of 5 in
CDCl3 showed broadened signals for the majority of the peaks,
which was attributed to an intramolecular dynamic process with
a rate intermediate in the NMR timescale at temperatures near
298 K. Relatively sharp 1H and 13C NMR spectra were measured
at 333 K, which were used for the structural confirmation of 5.
Further variable-temperature 1H and 13C measurements, including
two-dimensional exchange-correlated spectroscopy,35 revealed the
presence of two conformations in the dynamic process. In partic-
Fig. 2 Experimental (top, in CDCl3, 333 K) and calculated (bottom)
600 MHz H NMR spectra of the free base of 6. Fifteen protons of the
five- and eight-membered aliphatic rings were included in the iterative
fittings of the experimental spectrum.
1
The scope of this method was then investigated with respect to
aromatic substituents, and the results are shown in Table 1.
As expected of an electrophilic cyclisation, electron-donating
substituents increased the rate of reaction and gave higher yields,
as exemplified by the p-tolyl and 3,4-dimethoxy analogues (5a and
5b respectively). The 2,5-dimethoxy 5c gave a much lower yield,
though the reaction was still fast and could be run at ambient
temperatures. Electron-withdrawing substituents both slowed the
reaction and gave lower yields. Thus the 4-Br 4e and 4-phenyl 4f
gave only poor yields of the benzazocinones 5e and 5f respectively.
None of the desired product could be detected from the 4-Cl
4d cyclisation. In all cases, where a poor yield was obtained a
significant quantity of insoluble, presumably polymeric material,
was produced. For the very electron-rich 4b, the cyclisation could
be achieved using 10 equivs. of TFA (1 h reflux, 90% yield).
ular, two sets of peaks were observed at 213 K in the 1H and 13
C
NMR spectra of 5 with the integral intensity ratio of 2.7:1. Proton
H-2, the bridgehead proton of the major conformer, appeared as
a doublet of doublets (J = 6.4 and 9.3 Hz), whereas that of the
minor conformer showed only a doublet (J = 7.0 Hz). Based upon
3
these values and the boundary values of the corresponding JHH
couplings predicted for L-prolines,36 the five-membered ring of the
major conformer is in the C4-exo conformation, whereas that of
the minor comformer is in the C4-endo conformation. Here we use
the previously suggested notation for L-proline conformations,36,37
where the endo-/exo-orientation of the C4 atom is determined
3
relative to the C2–C1 bond. Overall, the JHH couplings of both
1
In the H and 13C NMR spectra of 5b and 5e at 213 K, again
the five- and eight-membered rings were in favour of a two-site
conformational equilibrium shown in Fig. 1, where the C4-exo-
C8-endo form is the preferred major conformer. The free energy
barrier for the conformational change from the C4-exo-C8-endo
conformer into the C4-endo-C8-exo conformer for 5 was estimated
to be 55 1 kJ mol-1 at the coalescence temperature of 266 K. For
the reverse interconversion from the C4-endo-C8-exo conformer
into the C4-exo-C8-endo conformer the free energy barrier was
estimated to be 53 1 kJ mol-1 at 266 K.
two sets of peaks were observed with the integral intensity ratios of
4.3:1 and 3.4:1 respectively. Similar to 5, the free energy barrier for
the conformational change from the C4-exo-C8-endo conformer
into the C4-endo-C8-exo conformer for 5e was estimated to be 56
1 kJ mol-1 at the coalescence temperature of 266 K. For the reverse
interconversion from the C4-endo-C8-exo conformer into the
Table 1 Synthesis of substitued hexahydrobenzazocin-3-ones 5a–f
Isolated
yield (%)
Cpd. no.
R
T (h)a
Cpd. no.
R
4a
4b
4c
4d
4e
4f
4-Me
4
1
5a
5b
5c
5d
5e
5f
14-Me
13,14-diMeO 80
12,15-diMeO 26
14-Cl
14-Br
14-Ph
75
3,4-diMeO
2,5-diMeO 21b
4-Cl
4-Br
4-Ph
18
18
0.5
0
17
25
a Time of reaction in CHCl3 heated under reflux. b At ambient tempera-
tures.
Fig. 1 A representation of the two conformers of 5 from NMR analysis.
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C4-exo-C8-endo conformer the free energy barrier was estimated
to be 53 1 kJ mol-1 at 266 K (Fig. 3).
Fig. 4 Structure of hexahydrobenzazocinone 5c as determined by X-ray
crystallography. ORTEP diagram (50% probability ellipsoids) showing the
crystallographic atom-numbering scheme.
readily prepared by mild acid hydrolysis of the amidoacetal. Thus
treatement of an acetone solution 4d–h with 1 M HCl solution for
15 min gave the intermediate N-acyl- 2-hydroxypyrrolidines 7d–h
in essentially quantitative yields (Scheme 3).
Previous experience had shown that N-acyl-2-hydroxy-pyrro-
lidines were too unstable to purify by column chromatography
and so 7d–i were used without further purification. Triflic acid
cyclisation of 7d–g gave higher yields of benzazocines 5d–g, than
previously obtained from the amides (yields quoted are the overall
yields from 4d–g). Cyclisation of the m-Br congener 7g gave almost
exclusively the 13-Br product 5g, with only a trace of a less polar
isomer, presumably the 15-Br, detectable by MS. Cyclisation of
the 4-methoxy lactam 7i gave only a trace (TLC, MS) of the
hexahydrobenzazocine, but an improved yield was obtained from
the 3-Br, 4-MeO lactam 7h as a single isomer. A similar low
yield was reported for the TiCl4-mediated cyclisation of 1-(4-
methoxyphenylacetyl)-2-methoxypyrrolidine to the pyrrolidino-
tetrahydroisoquinoline.38
Fig. 3 The temperature dependence of the 1H NMR spectra of 5e (CDCl3,
400 MHz).
A sample of 5c was submitted for X-ray analysis, which
confirmed the structure as the benzazocin-3-one (Fig. 4). Unlike
1
the other benzazocinones, 5c showed sharp H and 13C NMR
3
spectra in CDCl3 at 298 K with the JHH-couplings indicating
of a single C4-exo-C8-endo conformer, in agreement with the
solid-state structure. Presumably the steric constraints of the 12-
and 15-substituents restricts the conformational freedom of the
8,5 system.
This methodology also works well for phenyl butyramides
substituted in the alkyl chain. Cyclisation of the 4,4-diphenyl-
butyric acid amide gave a good yield of the phenyl-substituted
benzazocinone, which from NMR, the isolated product was a
mixture of isomers in a ratio of 20:1 (Scheme 4). The major
In our previous paper,14 a higher yield of tetrahydro-isoqui-
nolinone was obtained from the N-acyl-2-hydroxy-pyrrolidine,
Scheme 3 Synthesis of the hexahydrobenzazocines 5d–i via the 2-hydroxypyrolidines 7d–i. Reagents and conditions: a) HCl, acetone, b) CF3SO3H,
CHCl3, heat.
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Scheme
4 Synthesis of benzazocine 8; Reagents and conditions:
a) (COCl)2, CH2Cl2, DMF, b) H2N(CH2)3CH(OEt)2, EtNMe2 (100%),
c) CF3SO3H, CHCl3, heat (73%).
Scheme 5 Synthesis of dibenzoazocines 12a and 12b: Reagents and
conditions: a) (COCl)2, CH2Cl2, DMF, b) H2N(CH2)3CH(OEt)2, EtNMe2
(100%), c) CF3SO3H, CHCl3, heat.
isomer 8 was isolated as a solid and its structure confirmed by
X-ray analysis (Fig. 5), which shows that the phenyl group is
in a pseudo-equatorial orientation ‘cis’ to the bridgehead C4
proton.
Fig. 6 Structure of hexahydro-dibenzazocinone 12a as determined by
X-ray crystallography. ORTEP diagram (50% probability ellipsoids)
showing the crystallographic atom-numbering scheme. There are two
independent molecules in the asymmetric unit and only one of these
is shown in the figure. The asymmetric unit was selected so that both
molecules have the same R-stereochemistry.
Fig. 5 Structure of hexahydro-benzazocinone 8 as determined by X-ray
crystallography. ORTEP diagram (50% probability ellipsoids) showing the
crystallographic atom-numbering scheme.
Both the attempted application of this methodology to the
synthesis of the 9-membered ring homologue from the 5-
phenylpentanoic acid amide 9 and the attempted cyclisation of the
4-phenylbutanoic acid amide of 5-aminopentananal diethylacetal
10 failed to give any cyclised products.
No formation of 6 was observed under the acidic conditions of
TFA or triflic acid 2 h in refluxing CHCl3, or 2 M aqueous HCl at
reflux for 24 h.
Ph(CH2)4CONH(CH2)3CH(OEt)2
9
Conclusion
Ph(CH2)3CONH(CH2)4CH(OEt)2 10
In conclusion, we have shown that pyrrolo-benzazocin-3-ones
can be readily prepared from the commercially available 4-
aminobutyraldehyde diethyl acetal and the appropriate carboxylic
acids in moderate to high yield via an intramolecular N-acyl
iminium ion cyclisation. For electron-withdrawing substituents,
pre-formation of the 2-hydroxy-pyrrolidine amides gave better
yields. Two series of pyrrolo-dibenzazocines were also prepared.
This method is not applicable for the synthesis of the 3-aza-
benzocyclononanes or the piperidino-benzazocines, nor was the
Pictet–Spengler cyclisation successful. Our future work will con-
centrate on further investigation of the scope of this methodology
and on the synthesis of 8-membered analogues of biologically
active tetrahydroisoquinolines and benzazepines, and it is our
belief that this chemistry will further open up the possibility of
8-membered rings for exploitation in, for example, chemical
library synthesis and drug discovery.
An alternative system was also evaluated where there is no
possibility for the formation of a 6-membered ring (Scheme 5).
The commercial a-phenyl-o-toluic acid was converted into the
4-aminobutyraldehyde diethylacetal amide derivative via the acid
chloride. Cyclisation with triflic acid afforded the tetracycle 12a
1
in an excellent yield. Both the H and 13C NMR spectra were
consistent with the proposed structure. The structure of 12a was
confirmed by an X-ray structural analysis (Fig. 6). Cyclisation
of the ortho-phenoxyamide derived from 11b also gave the cyclic
product 12b, though in a slightly lower yield.
Although it is well known that acyliminium ions are more
electrophilic than iminium ions,39 for comparison the Pictet–
Spengler type cyclisation of the amine 13, prepared from 4 by
reduction with LAH, to 6 was investigated.
Ph(CH2)4NH(CH2)3CH(OEt)2 13
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into CH2Cl2 (3 ¥ 50 ml). The organic extracts were dried (MgSO4)
and filter through a SiO2 bed (~20 g), washing with Et2O until no
more non-polar material was extracted. The combined washings
were evaporated in vacuo to give 3.1 g of pale yellow oil. 1H NMR
(300 MHz, CDCl3): d 1.95 (quintet, 2H, J = 7 Hz), 2.39 (t, 2H, J =
7 Hz), 2.65 (t, 2H, J = 7 Hz), 7.10–7.21 (m, 2H), 7.31–7.40 (m, 2H
including 7.35, d, 1H, J = 1.5 Hz). 13C NMR and DEPT (75 MHz,
CDCl3) d = 25.6 (CH2), 33.3 (CH2), 34.6 (CH2), 122.5 (C), 127.2
(CH), 129.3 (CH), 130.0 (CH), 133.6 (CH), 143.6 (C), 180.0 (C).
Experimental
All reagents were commercially available, unless specified, 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. Solution 1H and 13C NMR spectra (Tables 2, 3
and 4) were recorded on Bruker NMR spectrometers AMX300,
Avance III 400, DRX500 and Avance III 600 equipped with
z-gradient facilities. H and 13C chemical shifts are given relative
1
to TMS. Unless otherwise specified, spectra were recorded at
Synthesis of 4-(3-bromo-4-methoxyphenyl)-butyric acid
1
298 K. The H spectra of 5b, 5c and 6 were analysed using full
lineshape analysis.40 Low temperature NMR measurements were
carried out for hexahydro-benzazocinones 5, 5b and 5e. The value
of the free energy of activation for 5 and 5e was calculated using
the procedure described previously.41
A solution bromine (0.52 ml, 10 mmol) in CHCl3 (10 ml) was
added, drop-wise to a stirred solution of 4-(4-methoxyphenyl)-
butyric acid (1.94 g, 10 mmol) in CHCl3 (30 ml) at ambient
temperature and the stirring was continued for 1 h. The solvent
was removed in vacuo and the residue triturated purified by
column chromatography on silica, eluting with CH2Cl2–10%
Et2O/CH2Cl2. and triturated with petrol to give 1.4 g of white
4-(3-Bromophenyl)-butyric acid
4-(3-Bromophenyl)-4-oxo-butyric acid42 (4.8 g) and KOH (3.6 g)
was dissolved in 35 ml ethylene glycol and hydrazine hydrate
(2.4 ml) added. The reaction mixture was heated to reflux (140 ◦C)
for 2 h, then heated to 220 ◦C (heating block temperature) to
distill out the H2O and excess hydrazine hydrate. After all the
distillation had ceased, the reaction mixture was heated for 1 h,
the cooled to room temperature, H2O added (100 ml) and conc.
HCl to acidic, then ice (50 g). On scratching with a glass rod, a solid
had formed which was collected, dissolved in Et2O (150 ml) and
the product extracted into 1 M NaOH (2 ¥ 50 ml). The aqueous
solution was acidified with 2 M HCl and the product extracted
◦
1
solid (50%). Mpt = 78–80 C; H NMR (300 MHz, CDCl3): d
1.95 (quintet, 2H, J = 7 Hz), 2.39 (t, 2H, J = 7 Hz), 2.65 (t, 2H,
J = 7 Hz), 7.10–7.21 (m, 2H), 7.31–7.40 (m, 2H including 7.35,
d, 1H, J = 1.5 Hz). 13C NMR and DEPT (75 MHz, CDCl3) d =
6.2 (CH2), 33.2 (CH2), 33.7 (CH2), 56.3 (CH3), 111.6 (C), 112.0
(CH), 128.4 (CH), 133.3 (CH), 134.9 (C), 154.3 (C), 180.0 (C).
General procedure for the synthesis of the amides
Oxalyl chloride (10 mmol) was added to a stirred solution of the
appropriate acid (10 mmol) in DCM (30 mL) and 1–2 drops of
Table 2 1H NMR chemical shifts (dH, ppm) of hexahydrobenzazocinones in CDCl3. The spectrum of 5c was measured at 298 K, all other spectra were
measured at 333 K. The structure shows the proton and carbon numbering used in the NMR assignments in Tables 2–4. The relative orientations of the
protons are defined relative to proton H-2c: “c” and “t” are used to denote protons with the cis and trans orientations relative to proton H-2c
Proton
5
5a
5b
5c
5d
5e
5f
6a
2c
3c
3t
4c
4t
5c
5t
8c
8t
5.03
2.40
2.07
1.87
1.91
3.87
3.43
2.49
2.26
1.70
1.95
2.66
2.96
7.05
7.16
7.14
7.12
4.98
2.40
2.06
1.86
1.91
3.87
3.44
2.48
2.24
1.66
1.95
2.48
2.92
6.93
6.97
2.29 (Me)
6.92
4.967
2.412
2.081
1.888
1.960
3.863
3.447
2.508
2.265
1.713
1.935
2.584
2.912
6.553
3.833 (OMe)
3.836 (OMe)
6.638
5.182
2.520
1.719
1.813
1.853
3.838
3.549
2.371
2.106
1.447
1.927
3.207
2.529
3.747 (OMe)
6.738
6.689
3.747 (OMe)
5.00
2.44
2.07
1.90
1.96
3.90
3.44
2.47
2.29
1.70
1.96
2.64
2.95
7.00
7.14
—
4.98
2.42
2.06
1.89
1.95
3.88
3.42
2.44
2.27
1.68
1.95
2.62
2.92
6.93
7.27
—
5.13
2.49
2.17
1.92
1.98
3.94
3.50
2.57
2.32
1.77
2.04
2.73
3.03
7.15
7.41
—
3.746
2.192
1.949
1.832
1.933
2.430
2.974
1.546
1.453
1.662
1.754
2.722
3.593
7.042
7.15
9c
9t
10c
10t
12
13
14
15
7.14
7.13
7.13
7.26
7.36
a 2.590 ppm (H-7c) and 2.611 ppm (H-7t).
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Table 3 Proton J-couplings (in Hz) of hexahydrobenzazocinones 5–5f and 6 in CDCl3. The spectrum of 5c was measured at 298 K, all other spectra
were measured at 333 K
Protons
5
5a
5b
5c
5d
5e
5f
6
2c–3c
2c–3t
3c–3t
3c–4t
3c–4c
3t–4c
3t–4t
4c–4t
4c–5c
4c–5t
4t–5c
4t–5t
7.1
7.1
-12.7
5.1
7.6
8.7
7.3
-12.6
8.6
8.1
4.1
7.1
7.1
-12.7
5.0
7.5
8.7
7.2
-12.5
8.5
8.1
4.2
6.99
6.98
-12.80
5.29
7.58
8.41
7.25
-12.63
8.42
8.12
4.41
6.15
9.69
-12.57
3.29
6.51
10.81
6.68
-12.41
8.65
7.1
7.1
-12.7
5.2
7.5
8.5
7.0
-12.7
8.4
7.9
4.3
7.1
7.1
-12.9
5.1
7.4
8.7
7.1
-12.6
8.4
8.2
4.2
7.1
7.1
-12.7
5.0
7.5
8.6
7.0
-12.6
8.5
8.3
4.3
7.55
7.74
-12.87
5.29
10.06
5.83
10.72
-12.54
8.63
3.74
7.68
9.06
3.44
7.45
8.1
8.1
7.85
7.9
8.0
8.1
8.38
5c–5t
8c–8t
8c–9c
8c–9t
8t–9c
8t–9t
9c–9t
9c–10c
9c–10t
9t–10c
9t–10t
10c–10t
Other
-12.2
-12.4
4.8
12.8
4.2
4.2
-13.0
4.0
11.7
5.0
3.9
-13.8
—
-12.2
-12.3
4.9
12.8
4.1
4.0
-12.8
4.9
11.9
4.9
3.9
-13.8
7.8 (12–13),
1.7 (13,15)
-12.17
-12.32
4.79
12.72
4.03
4.18
-13.41
3.71
11.82
5.04
3.80
-13.96
—
-12.21
-11.88
5.38
13.27
2.61
4.47
-13.06
3.90
13.55
3.04
4.09
-13.29
8.94 (13–14)
-12.2
-12.5
4.8
12.7
4.1
4.1
-12.8
3.8
11.8
5.0
3.9
-13.9
~8 (12–13),
2.2 (13,15)
-12.1
-12.5
4.7
12.8
4.0
3.9
-12.8
3.9
11.9
5.0
3.9
-13.9
~8 (12–13),
2.1 (13,15)
-12.2
-12.4
4.9
12.8
4.1
4.1
-12.8
3.9
11.9
4.7
3.9
-13.8
7.9 (12–13),
2.0 (13,15)
-9.14
-15.00
11.97
3.34
3.35
5.37
-13.62
6.71
5.31
5.32
8.85
-12.82
-12.57 (7c–7t), 3.09 (7c–8c),
5.27 (7c–8t), 0.85 (7c–9t),
11.28 (7t–8c), 3.13 (7t–8t)
Table 4 13C NMR chemical shifts (dC, ppm) of hexahydrobenzazocinones 5–5f and 6 in CDCl3. The spectrum of 5c was measured at 298 K, all other
spectra were measured at 333 K. The values of 1JCH couplings (in Hz) are also included in brackets for 5c
Carbon
5
5a
5b
5c
5d
5e
5f
6
1-Cq
2-CH
3-CH2
4-CH2
5-CH2
7
8-CH2
9-CH2
10-CH2
11-Cq
12
140.54
62.80
36.83
22.75
45.94
172.48
33.81
27.37
32.62
138.16
131.49
126.57
127.61
126.90
—
140.35
62.93
37.12
22.77
46.01
172.50
33.67
27.60
132.75
62.53
36.91
22.80
46.04
172.61
33.91
27.61
32.22
130.96
115.20
148.66
147.89
111.61
56.54 (13-OMe),
56.24 (14-OMe)
130.09
142.38
62.35
36.78
22.66
45.93
172.22
33.59
27.22
31.93
136.60
132.81
127.58
132.29
126.91
—
142.85
62.40
36.99
22.77
46.08
172.32
33.63
27.25
32.06
137.18
133.22
130.67
120.29
129.95
—
140.90
63.11
37.33
22.92
46.15
172.65
33.80
27.52
32.32
137.25
132.17
126.38
141.04
125.84
141.08
65.65
34.16
22.71
55.30
54.01
24.67
30.17
32.98
140.19
130.50
125.92
126.86
127.13
59.44 (145)
36.09 (134)
22.50 (131)
46.81 (143)
172.71
32.26 (131)
25.74 (132)
21.01 (131)
127.48
32.03
135.01
131.46
128.31
135.97
127.63
20.97 (14-Me)
151.02
13
14
15
Other
109.47 (159)
108.31 (159)
150.19
56.21(143) (12-OMe),
55.75 (143) (15-OMe)
139.78 (i-Ph), 127.13 (o-Ph),
128.96 (m-Ph), 127.50 (p-Ph)
DMF were added. After stirring at ambient temperatures for 2 h,
by which time gas evolution had ceased, the solvent was removed
by rotary evaporation in vacuo. The crude acid chloride was re-
dissolved in DCM (20 mL) and was added, dropwise, to a stirred,
cooled (0 ◦C) solution of 4-aminobutyraldehyde diethyl acetal
(10 mmol) and Et2NMe (12 mmol) in Et2O (50 mL) over 5 min.
The stirred reaction mixture was warmed to room temperature
over 1 h. A 1 M aqueous solution of NaHCO3 (30 mL) was then
added and the mixture transferred to s separating funnel, shaken
then allowed to settle. The lower aqueous layer was separated and
the organic layer washed with brine (30 mL). The organic layer
was collected, dried (K2CO3), filtered and the filtrate concentrated
in vacuo, then dried under high vacuum to give the essentially
pure amides (>98% by HPLC) which were used without further
purification.
2-Biphenyl-2-yl-N-(4,4-diethoxybutyl)acetamide (1). Isolated
1
as an oil (95% yield). H NMR (300 MHz, CDCl3): d 1.17 (t,
6H, J = 7 Hz), 1.40–1.56 (m, 4H), 3.16 (dt, 2H, J = 7, 13 Hz),
3,37–3.66 (m, 4H), 3.52 (s, 2H), 4.42 (t, 1H, J = 5 Hz), 5.35 (brs,
1H), 7.24–7.48 (m, 9H): 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.3 (CH3), 24.6 (CH2), 30.8 (CH2), 39.3 (CH2), 41.4 (CH2),
61.3 (CH2), 102.5 (CH), 127.3 (CH), 127.4 (CH), 128.0 (CH),
172 | Org. Biomol. Chem., 2009, 7, 167–177
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129.1 (CH), 130.5 (CH), 130.7 (CH), 132.5 (C), 140.9 (C), 142.6
(C), 170.9 (C).
2.11 (t, 2H, J = 7 Hz), 2.57 (t, 2H, J = 7.5 Hz), 3.22 (quartet,
2H, J = 6.5 Hz), 3.39–3.52 (m, 2H), 3.56–3.69 (m, 2H), 4.45 (t,
1H, J = 5 Hz), 5.91 (brs, 1H), 7.02 (d, 2H, J = 8 Hz), 7.36 (d,
2H, J = 8 Hz). 13C NMR and DEPT (75 MHz, CDCl3) d =
15.3 (CH3), 24.6 (CH2), 26.9 (CH2), 31.1 (CH2), 34.6 (CH2), 35.7
(CH2), 39.2 (CH2), 61.5 (CH2), 102.7 (CH), 119.7 (C), 130.2 (CH),
131.4 (CH), 140.5 (C), 172.4 (C).
N-(4,4-Diethoxybutyl)-4-phenyl-butyramide (4). Isolated as an
oil (100% yield). 1H NMR (300 MHz, CDCl3): d 1.17 (t, 6H, J =
6 Hz), 1.48–1.66 (m, 4H), 1.94 (quintet, 2H, J = 7 Hz), 2.13 (t,
2H, J = 7 Hz), 2.62 (t, 2H, J = 7 Hz), 3.22 (quartet, 2H, J =
6 Hz), 3.39–3.52 (m, 2H), 3.56–3.68 (m, 2H), 4.45 (t, 1H, J =
5.5 Hz), 5.82 (brs, 1H), 7.10–7.20 (m, 3H), 7.21–7.29 (m, 2H): 13
C
N-(4,4-Diethoxybutyl)-4-(4-biphenyl)-butyramide
(4f). Iso-
lated as an oil (100%). 1H NMR (300 MHz, CDCl3): d = 1.12 (t,
6H, J = 7 Hz), 1.45–1.66 (m, 4H), 1.99 (quintet, 2H, J = 7 Hz),
2.18 (t, 2H, J = 7 Hz), 2.68 (t, 2H J = 7 Hz), 3.25 (quartet,
2H, J = 6.5 Hz), 3.38–3.53 (m, 2H), 3.56–3.68 (m, 2H), 4.49 (t,
1H, J = 7.5 Hz), 5.83 (brs, 1H), 7.19–7.59 (m, 9H); 13C NMR and
DEPT (75 MHz, CDCl3) d = 15.4 (CH3), 24.6 (CH2), 27.1 (CH2),
31.1 (CH2), 34.9 (CH2), 36.0 (CH2), 39.3 (CH2), 61.5 (CH2), 102.7
(CH), 127.0 (CH), 127.1 (CH), 128.7 (CH), 128.9 (CH), 138.9
(C), 140.7 (C), 141.0 (C), 172.7 (C).
NMR and DEPT (75 MHz, CDCl3) d = 15.3 (CH3), 24.6 (CH2),
27.2 (CH2), 31.1 (CH2), 35.2 (CH2), 36.0 (CH2), 39.2 (CH2),61.5
(CH2), 102.7 (CH), 125.9 (CH), 128.4 (CH), 128.5 (CH), 141.5
(C), 172.7 (C).
N-(4,4-Diethoxybutyl)-4-(4-methylphenyl)-butyramide (4a).
Isolated as an oil (100%). 1H NMR (300 MHz, CDCl3): d = 1.19
(t, 6H, J = 7 Hz), 1.53–1.70 (m, 4H), 1.93 (quin., 2H, J = 8 Hz),
2.14 (t, 2H, J = 8 Hz), 2.31 (s, 3H), 2.60 (t, 2H, J = 8 Hz), 3.24
(quartet, 2H, J = 6 Hz), 3.43–3.55 (m, 2H), 3.57–3.70 (m, 2H),
4.47 (t, 1H, J = 5.5 Hz), 5.62 (brs, 1H), 7.04 (d, 2H, J = 5.5 Hz),
7.08 (d, 2H, J = 5.5 Hz): 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.3 (CH3), 21.0 (CH3), 24.6 (CH2), 27.3 (CH2), 31.1 (CH2),
34.8 (CH2), 36.0 (CH2), 39.2 (CH2), 61.5 (CH2), 102.7 (CH), 128.4
(CH), 129.1 (CH), 135.4 (C), 138.4 (C), 172.7 (C).
N-(4,4-Diethoxybutyl)-4-(3-bromophenyl)-butyramide (4g).
Isolated as an oil (100%). 1H NMR (300 MHz, CDCl3) d = 1.18
(t, 6H, J = 7 Hz), 1.49–1.67 (m, 4H), 1.92 (quin, 2H, J = 7 Hz),
2.13 (t, 2H, J = 7 Hz), 2.60 (t, 2H, J = 7.5 Hz), 3.24 (quartet,
2H, J = 6.5 Hz), 3.39–3.52 (m, 2H), 3.56–3.69 (m, 2H), 4.46 (t,
1H, J = 5 Hz), 5.69 (brs, 1H), 7.08–7.16 (m, 2H), 7.26–7.33 (m,
2H): 13C NMR and DEPT (75 MHz, CDCl3) d = 15.3 (CH3),
24.6 (CH2), 26.9 (CH2), 31.1 (CH2), 34.9 (CH2), 35.7 (CH2), 39.2
(CH2), 61.5 (CH2), 102.7 (CH), 122.4 (C), 127.2 (CH), 129.1
(CH), 130.0 (CH), 131.5 (CH), 143.9 (C), 172.3 (C).
N -(4,4-Diethoxybutyl)-4-(3,4-dimethoxy)phenyl-butyramide
1
(4b). Isolated as an oil (100%). H NMR (300 MHz, CDCl3):
d = 1.05–1.22 (m, 6H), 1.45–1.66 (m, 4H), 1.81–1.99 (m, 2H),
2.06–2.19 (m, 2H), 2.46–2.62 (m, 2H), 3.15–3.30 (m, 2H), 3.35–
3.50 (m, 2H), 3.51–3.66 (m, 2H), 3.77–3.88 (m, 6H), 4.36–3.49
(m, 1H), 5.63–5.91 (brs, 1H), 6.59–6.80 (m, 3H). 13C NMR and
DEPT (75 MHz, CDCl3) d = 15.3 (CH3), 24.6 (CH2), 27.4 (CH2),
31.1 (CH2), 34.8 (CH2), 35.9 (CH2), 39.2 (CH2), 55.8 (CH3), 55.9
(CH3), 61.5 (CH2), 102.7 (CH), 111.2 (CH), 111.8 (CH), 120.3
(CH), 134.2 (C), 147.2 (C), 148.8 (C), 172.7 (C).
N-(4,4-Diethoxybutyl)-4-(3-bromo-4-methoxyphenyl)-butyra-
mide (4h). Isolated as an oil (100%). 1H NMR (500 MHz,
CDCl3): d = 1.16 (t, 6H, J = 7 Hz), 1.51–1.65 (m, 4H), 1.88 (quin,
2H, J = 7 Hz), 2.11 (t, 2H, J = 7 Hz), 2.53 (t, 2H, J = 7.5 Hz), 3.24
(quartet, 2H, J = 6.5 Hz), 3.40–3.49 (m, 2H), 3.55–3.64 (m, 2H),
3.83 (s, 3H), 4.45 (t, 1H, J = 5 Hz), 5.76 (brs, 1H), 6.78 (d, 1H, J =
8.5 Hz), 7.04 (dd, 1H, J = 8.5, 2.0 Hz), 7.32 (d, 1H, J = 2.0 Hz).:
13C NMR and DEPT (125 MHz, CDCl3) d = 15.38 (CH3), 24.62
(CH2), 27.23 (CH2), 31.13 (CH2), 34.00 (CH2), 35.80 (CH2),
39.28 (CH2), 56.33 (CH3), 61.56 (CH2), 102.73 (CH), 111.45 (C),
112.02 (CH), 128.46 (CH), 135.31 (CH), 135.31 (C), 154.17 (C),
172.58 (C).
N -(4,4-Diethoxybutyl)-4-(2,5-dimethoxy)phenyl-butyramide
1
(4c). Isolated as an oil (100%). H NMR (300 MHz, CDCl3):
d = 1.17 (t, 6H, J = 7 Hz), 1.52–1.66 (m, 4H), 1.89 (quintet,
2H, J = 7.5 Hz), 2.16 (t, 2H, J = 7.5 Hz), 2.60 (t, 2H, J = 7.5 Hz),
3.24 (q, 2H, J = 6 Hz), 3.43–3.50 (m, 2H), 3.58–3.75 (m, 2H),
3.73 (s, 3H), 3.75 (s, 3H), 4.45 (t, 1H, J = 5.5 Hz), 5.75 (brs,
1H). 13C NMR and DEPT (75 MHz, CDCl3) d = 15.38 (CH3),
24.75 (CH2), 25.96 (CH2), 29.82 (CH2), 31.14 (CH2), 36.29 (CH2),
39.27 (CH2), 55.72 (CH3), 56.00 (CH3), 61.48 (CH2), 102.74 (CH),
111.26 (CH), 111.38 (CH), 116.42 (CH), 131.26 (C), 151.80 (C),
153.57 (C), 172.93 (C).
N-(4,4-Diethoxybutyl)-4-(4-methoxyphenyl)-butyramide (4i).
Isolated as an oil (100%) 1H NMR (300 MHz, CDCl3): d = 1.17
(t, 6H, J = 7 Hz), 1.45–1.66 (m, 4H), 1.89 (quintet, 2H, J = 7 Hz),
2.12 (t, 2H J = 7 Hz), 2.55 (t, 2H, J = 7 Hz), 3.22 (quartet, 2H,
J = 6 Hz), 3.38–3.53 (m, 2H), 3.56–3.68 (m, 2H), 3.75 (s, 3H),
4.45 (t, 1H, J = 5 Hz), 5.79 (brs, 1H), 6.79 (d, 2H, J = 8 Hz), 7.06
(d, 2H, J = 8 Hz); 13C NMR and DEPT (75 MHz, CDCl3) d =
15.3 (CH3), 24.6 (CH2), 27.4 (CH2), 31.1 (CH2), 34.3 (CH2), 35.9
(CH2), 39.2 (CH2), 55.3 (CH3), 61.5 (CH2), 102.7 (CH), 113.8
(CH), 129.4 (CH), 133.6 (C), 157.8 (C), 172.8 (C).
N-(4,4-Diethoxybutyl)-4-(4-chlorophenyl)-butyramide (4d).
Isolated as an oil (100%). 1H NMR (300 MHz, CDCl3): d = 1.18
(t, 6H, J = 7 Hz), 1.45–1.66 (m, 4H), 1.81–1.99 (m, 2H), 2.12 (t,
2H J = 7 Hz), 2.59 (t, 2H, J = 7 Hz), 3.25 (qt, 2H, J = 6.5 Hz),
3.38–3.53 (m, 2H), 3.56–3.68 (m, 2H), 4.44 (t, 1H, J = 7.5 Hz),
5.68 (brs, 1H), 7.08 (d, 2H, J = 8 Hz), 7.22 (d, 2H, J = 8 Hz). 13
C
NMR and DEPT (75 MHz, CDCl3) d = 15.3 (CH3), 24.6 (CH2),
27.0 (CH2), 31.1 (CH2), 34.5 (CH2), 35.7 (CH2), 39.2 (CH2), 61.5
(CH2), 102.7 (CH), 128.4 (CH), 129.8 (CH), 131.6 (C), 140.0 (C),
172.4 (C).
N-(4,4-Diethoxybutyl)-4,4-diphenyl-butyramide. Isolated as
1
an oil (88%) H NMR (300 MHz, CDCl3): d = 1.18 (t, 6H, J =
7 Hz), 1.45–1.66 (m, 4H), 2.07 (t, 2H, J = 7 Hz_), 2.39 (qu,
2H, J = 7 Hz), 3.21 (quartet, 2H, J = 6.5 Hz), 3.38–3.53 (m,
2H), 3.56–3.68 (m, 2H), 3.91 (t, 1H, J = 8 Hz), 4.46 (t, 1H, J =
7.5 Hz), 5.57 (brs, 1H), 7.10–7.32 (m, 10H). 13C NMR and DEPT
(75 MHz, CDCl3) d = 15.3 (CH3), 24.6 (CH), 31.1 (CH2), 31.2
N-(4,4-Diethoxybutyl)-4-(4-bromophenyl)-butyramide (4e).
Isolated as an oil (100%). 1H NMR (300 MHz, CDCl3): d = 1.17
(t, 6H, J = 7 Hz), 1.49–1.67 (m, 4H), 1.90 (quin, 2H, J = 7 Hz),
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(CH2), 35.0 (CH2), 39.2 (CH2), 50.6 (CH), 61.4 (CH2), 102.7
(CH), 126.3 (CH), 127.9 (CH), 128.5 (CH), 144.3 (C), 172.4 (C).
General procedure for the triflic acid-mediated cyclisation
A solution of the acetal (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 temperatures, water (20 ml) was added. 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 that were separated
by column chromatography on silica.
5-Phenyl-pentanoic acid (3,3-diethoxybutyl)-amide (9). Iso-
1
lated as an oil (95%): H NMR (300 MHz, CDCl3): d = 1.18
(t, 6H, J = 7 Hz), 1.50–1.73 (m, 8 H), 2.15 (t, 2H, J = 7 Hz), 2.61
(t, 2H, J = 7 Hz), 3.23 (q, 2H, J = 6 Hz), 3.40–3.53 (m, 2H), 3.55–
3.69 (m, 2H), 4.46 (t, 1H, J = 5 Hz), 5.71 (brs, 1H), 7.12–7.19 (m,
3H), 7.22–7.27 (m, 2H). 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.3 (CH3), 24.6 (CH2), 25.4 (CH2), 31.1 (CH2), 35.7 (CH2),
36.7 (CH2), 39.2 (CH2), 61.5 (CH2), 102.7 (CH), 125.7 (CH), 128.3
(CH), 128.4 (CH), 142.2 (C), 172.8 (C).
7-Phenyl-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-
one (2). Reaction heated to reflux for 3 h, purified by elution with
1:1 CH2Cl2/Et2O to 2%MeOH/Et2O and fraction 2 isolated as a
solid from trituration with Et2O (64%): mpt 157–9 ◦C. HRMS The-
oretical Mass: 263.12551, found: 263.12589. 1H NMR (300 MHz,
CDCl3): d = 1.91–2.25 (m, 3H), 2.61–2.79 (m, 1H), 3.41–3.55 (m,
2H), 3.63 (d, 1H, J = 18 Hz), 3.66–3.77 (m, 1H), 4.63–4.77 (m,
1H), 7.15–7.45 (m, 8H). 13C NMR and DEPT (75 MHz, CDCl3):
d = 23.4 (CH2), 31.7 (CH2), 37.0 (CH2), 44.8 (CH2), 59.7 (CH),
123.2 (CH), 126.6 (CH), 127.4 (CH), 128.4 (CH), 129.1 (CH),
129.2 (CH), 130.8 (C), 136.8 (C), 140.2 (C), 140.9 (C), 167.7 (C).
N-(5,5-Diethoxypentyl)-4-phenyl-butyramide (10). Isolated as
an oil (100%) 1H NMR (300 MHz, CDCl3): d = 1.18 (t, 6H, J =
7 Hz), 1.32–1.67 (m, 6H), 1.95 (quintet, 2H, J = 7.4 Hz), 2.15 (t,
2H, J = 7.4 Hz), 2.64 (t, 2H, J = 7.4 Hz), 3.22 (q, 2H, J = 6 Hz),
3.40–3.55 (m, 2H), 3.56–3.71 (m, 2H), 4.45 (t, 1H, J = 5.6 Hz), 5.50
(brs, 1H), 7.13–7.23 (m, 3H), 7.24–7.31 (m, 2H). 13C NMR and
DEPT (75 MHz, CDCl3) d = 15.3 (CH3), 22.1 (CH2), 27.2 (CH2),
29.5 (CH2), 33.3 (CH2), 35.2 (CH2), 36.0 (CH2), 39.4 (CH2), 61.1
(CH2), 102.8 (CH), 125.9 (CH), 128.4 (CH), 128.5 (CH), 141.5
(C), 172.6 (C).
1,2,3,6,10b-Pentahydro-1H-pyrrolo[2,1-a]-dibenzo[c,e]azocin-5-
one (3). Reaction heated to reflux for 3 h, purified by elution with
1:1 CH2Cl2/Et2O to 2%MeOH/Et2O and as fraction 1 isolated
as an oil (29%). HRMS Theoretical Mass: 263.12551: found:
263.12567. 1H NMR (300 MHz, CDCl3): d = 1.66–1.86 (m, 1H),
1.98–2.20 (m, 2H), 2.35–2.50 (m, 1H), 3.12 (d, 1H, J = 15 Hz),
3.57 (d, 1H, J = 15 Hz), 3.60–3.80 (m, 2H), 4.27 (t, 1H, J = 8 Hz),
7.25–7.55 (m, 8H). 13C NMR and DEPT (75 MHz, CDCl3): d =
23.4 (CH2), 33.6 (CH2), 43.3 (CH2), 48.4 (CH2), 53.5 (CH2), 56.7
(CH), 126.0 (CH), 127.5 (CH), 127.7 (CH), 127.9 (CH), 128.3
(CH), 128.5 (CH), 128.6 (CH), 130.0 (CH), 132.6 (C), 137.1 (C),
141.2 (C), 142.6 (C), 168.7 (C).
2-Benzyl-N-(4,4-diethoxybutyl)benzamide (11a). Isolated as
an oil (100%) 1H NMR (300 MHz, CDCl3): d = 1.16 (t, 6H, J =
7 Hz), 1.45–1.65 (m, 4H), 3.30 (q, 2H, J = 6 Hz), 3.35–3.50 (m,
2H), 3.53–3.68 (m, 2H), 4.17 (s, 2H), 4.43 (t, 1H, J = 5.3 Hz),
5.90 (brs, 1H), 7.07–7.37 (m, 9H). 13C NMR and DEPT (75 MHz,
CDCl3) d = 15.3 (CH3), 24.4 (CH2), 31.1 (CH2), 38.9 (CH2), 39.6
(CH2), 61.4 (CH2), 102.6 (CH), 126.0 (CH), 126.3 (CH), 127.1
(CH), 128.4 (CH), 129.0 (CH), 130.9 (CH), 137.0 (C), 138.8 (C),
140.9 (C), 170.0 (C).
N-(4,4-Diethoxybutyl)-2-phenoxybenzamide (11b). Isolated as
1
an oil (95%). H NMR (300 MHz, CDCl3): d = 1.13 (t, 3H, J =
7 Hz), 1.14 (t, 3H, J = 7 Hz), 1.53–1.67 (m, 4H), 3.30–3.61 (m,
6H), 4.41–4.40 (m, 1H), 6.80 (dd, 1H, J = 8.2, 1.7 Hz), 7.00–7.04
(m, 2H), 7.13–7.20 (m, 2H), 7.29–7.41 (m, 3H), 7.69 (brs, 1H), 8.20
(dt, 1H, J = 7.8, 1.5 Hz). 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.3 (CH3), 24.7 (CH2), 30.9 (CH2), 39.5 (CH2), 61.1 (CH2),
102.5 (CH), 118.4 (CH), 119.4 (CH), 123.7 (CH), 124.3 (C), 124.6
(CH), 130.1 (CH), 132.2 (CH), 132.5 (CH), 155.3 (C), 155.6 (C),
164.7 (C).
6-Aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-trien-7-one
(5). Reaction heated to reflux for 4 h, purified by elution with
Et2O-2% MeOH/Et2O, isolated as an oil (70% yield). HRMS
theoretical 215.13047, found 215.13000: FTIR (film) 2947, 2873,
1624, 1455, 1420, 754 cm-1.
14-Methyl-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-7-one (5a). Reaction heated to reflux for 4 h, purified by
elution with Et2O-2% MeOH/Et2O, isolated as an oil (70% yield).
HRMS Theoretical Mass: 229.14611, found 229.14545.
General procedure for the synthesis of the
2-hydroxypyrrolidino-lactams 7d–h
13,14-Dimethoxy-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),
12,14-trien-7-one (5b). From the acetal at reflux for 1 h, purified
by elution with Et2O-2% MeOH/Et2O, isolated as a white
solid, recrystallised from EtOAc/petrol (80% yield), m. pt. 116–
7 ◦C. HRMS Theoretical Mass: 275.15160, found 275.15154.
A solution of the 4,4-diethoxybutyl butyramide (3 mmol) in
acetone (50 ml) and 1 M HCl (12 ml) was allowed to stand at
room temperature for 30 min., by which time TLC showed no
starting material remaining. The reaction mixture was basified
with 1 M NaHCO3 solution (30 ml) and the acetone removed
under reduced pressure on a rotary evaporator. The product was
extracted from the aqueous residue with CH2Cl2 (3 ¥ 50 ml).
The combined organic extracts were dried (K2CO3), filtered and
evaporated to give the 2-hydroxypyrrolidino-lactam, used without
further purification. NMR analysis showed them to be a complex
mixture of ~20% aldehyde and amide rotomers.
12,15-Dimethoxy-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),
12,14-trien-7-one (5c). Isolated from the acetal at room temper-
ature for 21 h, purified by elution with Et2O-2% MeOH/Et2O,
isolated as a white solid, recrystallized from EtOAc/petrol (26%
yield), m. pt. 126–7 ◦C. HRMS Theoretical Mass: 275.15160,
found 275.15102. FTIR (solid) 1634, 1471, 1417, 1252, 1141, 1090,
784, 718 cm-1.
174 | Org. Biomol. Chem., 2009, 7, 167–177
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14-Chloro-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-7-one (5d). Prepared from the 2-hydroxypyrrolidine, heated
to reflux for 18 h, purified by elution with Et2O-2% MeOH/Et2O,
isolated as an oil (59% yield). HRMS: Theoretical Mass:
249.09149, found 249.09081.
hygroscopic gum. A sample was treated with 1 equivalent of picric
acid (35% water) in ethanol to give the picrate, (m pt 162–4 ◦C).
(2R,10R)(2S,10S)-10-Phenyl-6-aza-tricyclo[9.4.0.0*2,6*] pen-
tadeca-1(15),11,13-triene-7-one (8). From the acetal at reflux
for 3 h, purified by elution with Et2O and the solid triturated
with petrol (73%), a small sample was re-crystallized from
14-Bromo-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-7-one (5e). Prepared from the 2-hydroxypyrrolidine, heated
to reflux for 18 h, purified by elution with Et2O-2% MeOH/Et2O,
isolated as an oil (55% yield). HRMS Theoretical Mass: 293.04098,
found 293.03969.
◦
1
CH2Cl2/petrol, m. pt. 162–4 C. H NMR (500 MHz, CDCl3)
at 332 K: d = 1.75–2.60 (m, 7H), 3.60–3.79 (m, 1H), 3.87 (dt,
1H, J = 9.5, 2.4 Hz), 4.53 (dd, 1H, J = 12.3, 3.2 Hz), 4.93 (dd,
1H, J = 10.9, 5.1 Hz), 6.71 (d, 1H, J = 6.8 Hz), 7.05–7.45 (m, 8H).
13C NMR and DEPT (125 MHz, CDCl3) at 332 K: d = 22.4 (CH2),
31.2 (CH2), 32.7 (CH2), 39.5 (CH2), 43.3 (CH), 46.9 (CH2), 65.8
(CH), 126.5 (CH), 126.6 (CH), 127.7 (CH), 127.9 (CH), 128.5
(CH), 128.7 (CH), 129.2 (CH), 138.9 (C), 141.0 (C), 142.9 (C),
172.3 (C).
14-Phenyl-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-7-one (5f). Prepared from the 2-hydroxypyrrolidine, heated
to reflux for 18 h, purified by elution with Et2O-2% MeOH/Et2O,
isolated as an oil (45% yield). HRMS Theoretical Mass: 291.16177;
found: 291.16191.
4b,5,6,7-Tetrahydro-14H-dibenzo[c,f ]pyrrolo[1,2-a]azocin-9-one
(12a). From the acetal at reflux for 3 h, purified by elution
with CH2Cl2–20% Et2O/CH2Cl2, isolated as a white solid,
recrystallised from EtOAc/petrol (95% yield), m. pt. 127–
13-Bromo-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-7-one (5g). From the 2-hydroxypyrrolidine, heated to reflux
for 18 h, purified by elution with Et2O-4% MeOH/Et2O, isolated
as white solid (Et2O/petrol)(60%yield). HRMS Theoretical Mass:
293.04098: found 293.04037. 1H NMR (500 MHz, CDCl3) at
332 K: d = 1.68–1.80 (brm, H-9), 1.87–2.11 (m, H-3,4,4,9), 2.26–
2.35 (brm, H-8), 2.40–2.52 (m, H-3, 8), 2.61–2.70 (brm, H-10),
2.96 (ddd, H-10, J = 3.8, 11.9, 13.8 Hz), 3.40–3.50 (brm, H-5),
3.90 (ddd, H-5, J = 4.1, 8.6, 12.4 Hz), 5.01 (t, H-2, J = 7 Hz),
7.02 (d, H-15, J = 8.3 Hz), 7.25 (d, H-12, J = 2.2 Hz), 7.32 (dd,
H-14, J = 2.2, 8.3 Hz). 13C NMR and DEPT (150 MHz, CDCl3)
at 332 K: d = 22.60, 26.99, 32.22, 33.48, 36.79, 45.88, 62.34 (2-C),
120.99 (C-13), 128.54 (C-15), 129.50 (C-14), 134.01 (C-12), 139.54
(C-1), 140.27 (C-11), 172.14 (C-7).
9
◦C. HRMS Theoretical Mass: 263.13046, found 263. 12983.
1H NMR (300 MHz, CDCl3): d = 1.80–2.17 (m, 3H), 2.55–2.71
(m, 1H), 3.23–3.30 (m, 1H), 3.79 (d, 1H J = 14.5 Hz), 3.99–4.13
(m, 1H), 4.3 (d, 1H, J = 14.5 Hz), 4.67 (d, 1H, J = 5.5 Hz),
7.12–7.41 (m, 7H), 7.52 (dd, 1H, J = 7, 1 Hz). 13C NMR and
DEPT (75 MHz, CDCl3): d = 23.0 (CH2), 29.0 (CH2), 41.0 (CH2),
44.4 (CH2), 60.6 (CH), 125.2 (CH), 125.6 (CH), 127.1 (CH), 127.2
(CH), 127.9 (CH), 129.6 (CH), 130.6 (CH), 131.2 (CH), 134.9
(C), 136.4 (C), 138.0 (C), 139.2 (C), 171.0 (C).
4b,5,6,7-Tetrahydro-14-oxa-dibenzo[c,f ]pyrrolo[1,2-a]azocin-9-
one (12b). From the acetal at reflux for 2 h, purified by
elution with CH2Cl2–10% Et2O/CH2Cl2, (66% yield), m. pt. 144–
6 ◦C. HRMS Theoretical Mass: 265.10973, found 265.10973. 1H
NMR (600 MHz, CDCl3): d = 1.85–1.96 (m, 6–1H), 1.96–2.04 (m,
5–1H), 2.04–2.10 (m, 6–1H), 2.62 (dd, 5–1H, J = 5.3, 12.8 Hz),
3.40–3.48 (m, 7–1H), 3.87–3.95 (m, 7–1H), 4.72 (d, 4d-1H, J =
6.8 Hz), 7.10–7.16 (m, 2H), 7.22 (d, 1H, J = 7.9 Hz), 7.27 (t,
1H, J = 7.9 Hz), 7.32–7.48 (m, 2H), 7.42 (dt, 1H, J = 7.9, 1.2 Hz),
7.58 (dd, 1H, J = 7.6, 1.2 Hz). 13C NMR and DEPT (150 MHz,
CDCl3): d = 23.18 (6-CH2), 28.75 (5-CH2), 45.17 (7-CH2), 58.79
(4b-CH), 122.57 (CH), 122.74 (CH), 124.71 (CH), 125.99 (CH),
126.29 (CH), 127.52 (CH), 129.22 (C), 129.50 (CH), 132.23 (CH),
132.61 (C), 152.82 (C), 157.63 (C), 168.08 (C).
13-Bromo-14-methoxy-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-
1(11),12,14-trien-7-one (5h). Isolated from the acetal at reflux for
1 h, purified by elution with Et2O-2% MeOH/Et2O, isolated as a
white solid, recrystallized from EtOAc/petrol (80% yield), m. pt.
116–7 ◦C. HRMS Theoretical Mass: 323.05154, found 323.05138.
1H NMR (600 MHz, CDCl3) at 331 K: d = 1.64–1.77 (brm, 1H),
1.87–2.03 (m, 3H), 2.04–2.13 (m, 1H), 2.26–2.34 (brm, 1H), 2.41–
2.52 (m, 2H), 2.54–2.2 (brm, 1H), 2.89 (ddd, 1H, J = 3.8, 12.1,
14 Hz), 3.46 (dt, 1H, J = 8.0, 12.0 Hz), 3.86 (s, 3H), 3.89 (ddd,
1H-5, J = 12.1, 8.6, 4.2 Hz), 5.00 (t, 1H, J = 7.1 Hz), 6.66 (s, 1H),
7.26 (s, 1H). 13C NMR and DEPT (150 MHz, CDCl3) at 333 K:
d = 22.86 (CH2), 27.62 (CH2), 31.24 (CH2), 33.43 (CH2), 46.30
(CH2), 56.61 (CH3), 63.01 (CH), 110.68 (C), 111.19 (CH), 131.89
(C), 136.06 (CH), 141.04 (C), 154.65 (C), 172.69 (C).
(4,4-Diethoxy-butyl)-(4-phenyl-butyl)-amine (13). A solution
of the amide 4 (2.0 g, 6.5 mmol) in dry THF (20 ml) was added to
a stirred solution of 1 M LAH (30 ml, 30 mmol) in THF (30 ml)
under argon at 0 ◦C and the reaction was heat under gentle reflux
for 24 h. The reaction mixture was cooled to 0 ◦C and H2O (1 ml),
then 2 M NaOH (2 ml) were carefully add and the reaction mixture
stirred until a white solid formed. Et2O (50 ml) was then addded,
the solid collected which was thoroughly washed with Et2O (4 ¥
25 ml). The combined organic filtrate and washings were dried
(K2CO3), filter and concentrate in vacuo to give a colourless oil:
1.9 g (~100%). 1H NMR (500 MHz, CDCl3): d = 1.19 (t, 6H, J =
7 Hz), 1.50–1.57 (m, 4H), 1.61–1.70 (m, 4H), 2.58–2.65 (m, 6H),
3.45–3.54 (m, 2H), 3.59–3.67 (m, 2H), 4.48 (t, 1H, J = 5.7 Hz),
7.14–7.18 (m, 3H), 7.24–7.28 (m, 2H); 13C NMR and DEPT
(125 MHz, CDCl3): d = 15.41 (CH3), 25.51 (CH2), 29.32 (CH2),
6-Aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(15),11,13-triene (6).
A solution of 6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),12,14-
trien-7-one (0.9 g, 4.2 mmol) in dry THF (5 ml) was added, drop-
wise, to a stirred solution of 1 M LiAlH4 (4.2 ml, 4.2 mmol) in
dry THF (20 ml) and the reaction mixture heated to reflux for
2 h. On cooling to 0 ◦C, 2 M NaOH (0.6 ml) was carefully added,
drop-wise, the reaction mixture stirred for 30 min. and then Et2O
(50 ml) was added. The white solid was removed, washed with Et2O
(2 ¥ 50 ml) and the combined organics dried (K2CO3), filtered
and concentrated in vacuo to give the title compound as an oil
(0.8 g, 88% yield). HRMS Theoretical Mass: 201.15120, found
201.15131. Attempts to form an HCl salt resulted in a sticky,
This journal is
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Org. Biomol. Chem., 2009, 7, 167–177 | 175
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29.83 (CH2), 31.54 (CH2), 35.92 (CH2), 49.89 (CH2), 49.94 (CH2),
61.06 (CH2), 61.16 (CH2), 102.90 (CH), 125.74 (CH), 128.40 (CH),
128.53 (CH), 142.56 (CH).
0.28 ¥ 0.18 mm3; Data collection method Bruker SMART APEX
CCD diffractometer w rotation with narrow frames q range
for data collection 2.63 to 28.30◦; Index rangesh -12 to 12, k
-13 to 13, l -20 to 21; Completeness to q = 26.00◦ 97.7%;
Reflections collected 11524; Independent reflections 6146 (Rint
=
Crystal data and structure refinement
0.0221); Reflections with F2>2s 5332; Absorption correction
semi-empirical from equivalents; Min. and max. transmission
0.9748 and 0.9857; Structure solution direct methods; Refinement
method Full-matrix least-squares on F2; Weighting parameters a,
b 0.1039, 0.3159; Data/restraints/parameters 6146/0/361; Final
R indices [F2>2s] R1 = 0.0520, wR2 = 0.1554; R indices (all data)
R1 = 0.0583, wR2 = 0.1641. Goodness-of-fit on F2 1.079; Largest
and mean shift/su 0.000 and 0.000; Largest diff. peak and hole
12,15-Dimethoxy-6-aza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),
12,14-trien-7-one (5c). Chemical formula C16H21NO3; Formula
weight 275.34; Temperature 150(2) K; Radiation, wavelength
˚
MoKa, 0.71073A; Crystalsystem, spacegroupmonoclinic, P21/c;
◦
˚
˚
Unit cell parameters a = 8.3263(9) A; a = 90 ; b = 18.599(2) A; b =
◦
◦
3
˚
˚
107.795(2) ; c = 9.2541(10) A; g = 90 ; Cell volume 1364.5(3) A
Z 4; Calculated density 1.340 g/cm3; Absorption coefficient m
0.092 mm-1; F(000) 592; Crystal colour and size colourless, 0.40 ¥
0.12 ¥ 0.02 mm3; Data collection method Bruker SMART APEX
CCD diffractometer w rotation with narrow frames; q range
for data collection 2.56 to 28.27◦; Index ranges h -10 to 11,
k -24 to 24, l -12 to 12; Completeness to q = 26.00◦ 99.4%;
-3
˚
0.476 and -0.433 e A .
Acknowledgements
The authors would like to thank GSK for funding and L. Harris
for the mass spectra.
Reflections collected 11463; Independent reflections 3261 (Rint
=
0.0276); Reflections with F2>2s 2760; Absorption correction
semi-empirical from equivalents; Min. and max. transmission
0.9641 and 0.9982; Structure solution direct methods; Refinement
method Full-matrix least-squares on F2; Weighting parameters a,
b 0.0681, 0.3291; Data/restraints/parameters 3261/0/181; Final
R indices [F2>2s] R1 = 0.0439, wR2 = 0.1168; R indices (all data)
R1 = 0.0519, wR2 = 0.1221; Goodness-of-fit on F2 1.066; Largest
and mean shift/su 0.000 and 0.000; Largest diff. peak and hole
References
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0.343 and -0.260 e A .
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˚
length MoKa, 0.71073 A; Crystal system, space group mon◦oclinic,
˚
P21/c; Unit cell parameters a = 7.6569(8) A a = 90 , b =
◦
◦
˚
˚
9.6582(11) A b = 90.423(2) , c = 20.404(2) A g = 90 ; Cell volume
3
3
˚
1508.9(3) A ; Z 4; Calculated density 1.283 g/cm ; Absorption
coefficient m 0.078 mm-1; F(000) 624; Crystal colour and size
colourless, 0.48 ¥ 0.46 ¥ 0.43 mm3; Data collection method Bruker
SMART APEX CCD diffractometer w rotation with narrow
frames; q range for data collection 3.34 to 28.29◦; Index ranges h
-10 to 10, k -12 to 12, l -26 to 26; Completeness to q = 26.00◦
99.3%; Reflections collected 12268; Independent reflections 3580
(Rint = 0.0327); Reflections with F2>2s 3271; Absorption correc-
tion semi-empirical from equivalents; Min. and max. transmission
0.9634 and 0.9671;Structure solution direct methods; Refinement
method Full-matrix least-squares on F2; Weighting parameters a,
b 0.0720, 0.4836; Data/restraints/parameters 3580/0/200; Final
R indices [F2>2s] R1 = 0.0440, wR2 = 0.1201; R indices (all
data) R1 = 0.0473, wR2 = 0.1231; Goodness-of-fit on F2 1.041;
Extinction coefficient 0.027(4); Largest and mean shift/su 0.000
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˚
and 0.000; Largest diff. peak and hole 0.402 and -0.248 e A .
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4b,5,6,7-Tetrahydro-14H-dibenzo[c,f ]pyrrolo[1,2-a]azocin-9-
one (12a). Chemical formula C18H17NO; Formula weight 263.33;
Temperature 150(2) K; Radiation, wavelength MoKa, 0.71073 A;
˚
¯
Crystal system, space group triclinic, P1; Unit cell parameters a =
◦
◦
˚
˚
9.3106(8) A a = 75.9490(10) b = 10.4150(9) A b = 88.8050(10)
◦
3
˚
˚
c = 16.0747(14) A g = 63.5860(10) ; Cell volume 1347.4(2) A
Z 4; Calculated density 1.298 g/cm3; Absorption coefficient m
0.080 mm-1; F(000) 560; Crystal colour and size colourless, 0.32 ¥
176 | Org. Biomol. Chem., 2009, 7, 167–177
This journal is
The Royal Society of Chemistry 2009
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