An investigation into the electrophilic cyclisation of N-acyl-pyrrolidinium ions: A facile synthesis of Pyrrolo-tetrahydroisoquinolones and Pyrrolo-benzazepinones

Article abstract of DOI:10.1039/b907400g

The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively. Electron-donating R substituents enhanced the rate of reaction and gave higher yields than electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and in lower yield.

Full text of DOI:10.1039/b907400g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
An investigation into the electrophilic cyclisation of N-acyl-pyrrolidinium
ions: a facile synthesis of pyrrolo-tetrahydroisoquinolones and
pyrrolo-benzazepinones†
Frank D. King,*a Abil E. Aliev,a Stephen Caddicka and Royston C. B. Copleyb
Received 14th April 2009, Accepted 10th June 2009
First published as an Advance Article on the web 9th July 2009
DOI: 10.1039/b907400g
The triflic acid-mediated cyclisation of N-arylmethyl- and N-arylethyl-acylpyrrolidinium ions gave
moderate to good yields of pyrrolo-tetrahydroisoquinolones and pyrrolo-benzazepinones respectively.
Electron-donating R substituents enhanced the rate of reaction and gave higher yields than
electron-withdrawing substituents. Substituents on the methyl or ethyl chain in general enhanced the
reaction, unless sterically encumbered. The equivalent acylpiperidinium ions cyclised much slower and
in lower yield.
Introduction
Results and discussion
Tetrahydroisoquinoline can be regarded as a privileged structure,1
in that it occurs in a number of pharmacologically active
molecules.2–10 We are therefore interested in developing synthetic
approaches to tetrahydroisoquinolines, and homologues, for use
in the generation of diverse compound collections for pharma-
cological testing. In an earlier paper, we described the synthesis
of the tetrahydroisoquinoline ( )-crispine A 2 via an aromatic
electrophilic cyclisation of an acylpyrrolidinium ion, generated in
situ from the readily available amide 1 (Scheme 1).11 Previously,
for this type of cyclisation the iminium ion precursors were
prepared by anodic oxidation of the pyrrolidine amide,12,13 and
2.1 Cyclisation of phenylacetamides
We began our investigation with the phenylacetamide 3, shown
in the generalised Scheme 2. The three possible precursors to the
iminium ion, the phenylacetamide 3, the hydroxypyrrolidine 4 and
the ethoxypyrrolidine 5, can all be synthesized by the procedure
described in our earlier paper.11 Thus, the hydroxy pyrrolidine 4
was readily prepared from 3 by mild aqueous acid hydrolysis. The
ethoxy-pyrrolidine 5 was obtained in moderate yield directly from
3 by treatment with a catalytic quantity of TFA in the presence of
4A molecular sieves, but the reaction was not reproducible. A more
reliable method was the conversion of 4 to 5 which was achieved
using TFA in the presence of 3A molecular sieves.11
the cyclisation was restricted to electron rich aromatics.12,14
A
single example of cyclisation onto an unsubstituted phenyl was
described, but no further work was reported.13 In this paper, we
describe our study of the electrophilic cyclisation of N-arylacetyl-
and the homologous N-3-arylpropionyl-pyrrolidinium ions with
less activated aromatic rings in order to investigate the scope and
utility of this reaction.
Scheme 2 The electrophilic cyclisation of N-acyl-pyrrolidinium ions to
give pyrrolo-tetrahydroisoquinolones. Reagents: a) acid (see Table 1)
Scheme 1 Synthesis of ( )-crispine A 2. Reagents and conditions: a)
CF3SO3H, CHCl3, heat, b) AlH3
The conversion of the 2-methoxy analogue of 5 into 7 had
previously been reported using conc. H2SO4.13 However, we
found that treatment of 5 with conc. H2SO4 gave no evidence
of the formation of the lactam 7, but instead gave a single
product in an 85% yield, for which the NMR spectrum was
complex and the mass spectrum indicated a molecular weight
consistent with the formation of a dimer of the iminium ion 6. An
X-ray diffraction study determined the structure to be 9 (Fig. 1),
presumably formed by addition of the N-acyl dihydropyrrole 8
to the iminium ion 6, followed by deprotonation (Scheme 3).
Although only one enantiomer was found in the X-ray structure,
chiral HPLC showed, as expected, that the bulk material of 9 was
aDepartment of Chemistry, University College London, 20 Gordon Street,
London, WC1H 0AJ, UK. E-mail: f.d.king@ucl.ac.uk
bGlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex, CM19 5AD, UK
† Electronic supplementary information (ESI) available: 1H NMR and
13C NMR for all compounds, and crystal structure details for 9. CCDC
reference number 727741. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b907400g
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Table 2 Triflic acid-mediated cyclisation of substituted phenylacetamido-
pyrrolidinesa
Comp.
R1
Time/h
0.5
R2
Yield (%)
Product
5a
3-MeO
10-MeO
8-MeO
8,9-diMeO
8,9-diMeO
9-Cl
9-MeO
9-Br
33
46
100
85
40
0
7a
7a¢
7b
7b
7c
7d
7e
Fig. 1 A view of a molecule of 9 from the crystal structure, showing the
numbering scheme employed. Anisotropic atomic displacement ellipsoids
for the non-hydrogen atoms are shown at the 50% probability level.
Hydrogen atoms are displayed with an arbitrarily small radius.
5b
5b
5c
5d
4e
3,4-diMeO
3,4-diMeO
4-Cl
4-MeO
4-Br
0.5
18b
6
6
1c
60
a A solution of the substrate was added over 10 min to a mixture of 10
equiv. of triflic acid in CHCl3 at reflux. b Reaction carried out at ambient
temperatures. c Reaction carried out in 1,2-dichloroethane at reflux.
yielding, it offers an advantage over 5 as the preferred precursor.
It was found that the lactam 7 was relatively unstable and rapidly
darkened on storage in air.
Following the success of this cyclisation with triflic acid, the
effect of substitution on the phenyl ring was investigated (Table 2).
Although triflic acid gave slightly lower yields than AlCl3, it was
chosen for investigation as the reaction work-up was simpler and
the crude products cleaner and easier to purify. The choice of
substituents was dictated by their electron-donating/withdrawing
character and their potential for further synthetic manipulation.
As expected, the results were consistent with those we would
expect from an electrophilic substitution. Thus, the 3-methoxy
5a cyclised rapidly and gave a high combined yield of the two
isomers formed by cyclisation onto the ortho- (7a) and para- (7a¢)
positions respectively. Interestingly, the ratio of 7a:7a¢ (0.7 : 1)
is different from that reported for the TiCl4-mediated cyclisation
of the 2-methoxypyrrolidinyl amide (0.35 : 1).12 Following this
result, we re-investigated the cyclisation of the 3,4-dimethoxy-
phenylacetamde 5b and an excellent yield of 7b was obtained, even
at ambient temperatures. As previously described for the AlCl3-
induced cyclisation of 5b,11 only one isomer was formed. Studies
were also carried out with electron-withdrawing substituents and
the 4-chloro analogue 5c required prolonged heating and gave
only a moderate yield of the lactam 7c. The 4-methoxy amide
5d gave no lactam, which is a similar outcome to the previously
reported TiCl4-mediated cyclisation.12 Cyclisation of the 4-bromo-
phenylacetyl-2-hydroxypyrrolidine 4e also required forcing condi-
tions, however a good yield of lactam 7e was obtained in a shorter
reaction time using the higher boiling solvent 1,2-dichloroethane
at reflux. This study shows that the electrophilic cyclisation of
the 1-phenylacetyl-2-ethoxy- or 2-hydroxy-pyrrolidines can be
achieved with electron-withdrawing substituents on the aromatic
ring. However, an alternative direct conversion of the acetal 3 into
the isoquinolone 7 would be more convenient than the current
three-step synthesis. We therefore investigated the cyclisation of
the 3,4-dimethoxy-phenyl-acetamide 3b and 7b was obtained an
80% yield (Table 3). With this result in hand, we further explored
the cyclisation of amido-acetals and the results of these studies are
presented in Table 3.
Scheme 3 Proposed reaction to form 9.
a 1 : 1 mixture of enantiomers. Similar dimerisations of cyclic
iminium ions have been reported.15,16
The formation of 8 requires the loss of a proton, so to minimise
this, stronger acids were investigated, including the Lewis acids
used for the synthesis of 2.11 The results are summarised in Table 1.
The Lewis acids TiCl4, BF3.OEt2, and the Brønsted acids
HBr/AcOH and MeSO3H all failed to give the desired lactam
7. However, the use of 2 equivalents of AlCl3 gave a good yield
of 7. Increasing the quantity of AlCl3 to 4 equivalents gave a
slightly lower yield. A 10-fold excess of triflic acid also gave a
good yield of 7 when 5 was added to a mixture of triflic acid in
CHCl3 heated under reflux. A smaller quantity of triflic acid, or the
addition of 5 at ambient temperatures, gave lower yields of 7 and
led to an increased quantity of 9. The progress of the reaction can
be monitored by thin layer chromatography (TLC) of a basified
aliquot of the reaction mixture. A non-polar product is rapidly
formed, which then disappears with time and is followed by the
production of either 9 or 7. Attempts to characterise this non-polar
intermediate were unsuccessful, as the compound decomposed
on attempted purification. However, we speculate that it is the
enamide 8. The 2-hydroxypyrrolidine 4 also underwent cyclisation
with triflic acid and, as the synthesis of 4 is simpler and higher
Table 1 Successful cyclisation conditions for the conversion of 4 or 5
into 7
Comp.
Acid
Equiv.
Yield (%)b
5
5
5
5
4
AlCl3
3.0
4.0
7
10
10
73
61
35
60
60
AlCl3
Triflica
Triflica
Triflica
a A solution of 4 or 5 was added over 10 min. to a mixture of triflic acid in
CHCl3 at reflux, then heated for 1 h. b Isolated yield of 7 after purification
by column chromatography.
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Table 3 Triflic acid-mediate cyclisations of substituted phenylacetamides
Comp.
R1
Time/ha R2
Product
Yield (%)
Scheme
4
Synthesis of the 6,9-dimethyl pyrrolo-tetrahydro-
isoquinolones 7p and 7p¢. Reagents and conditions: a) CF3SO3H,
CHCl3, heat.
3
H
0.5
0.5
18
H
7
60
80
45
55
45
26
20
0
3b
3c
3e
3,4-diMeO
4-Cl
4-Br
8,9-diMeO
9-Cl
9-Br
8-Br
10-Br
7b
7c
7e
7f
18
an NMR study, for the more polar isomer, an nuclear Overhauser
effect (NOE) was observed between the methyl and the bridgehead
proton, which is only possible if the methyl group were ‘cis’ to the
bridgehead proton 7p in the boat conformation of the central six-
membered ring. In contrast, for the less polar isomer 7p¢, no such
NOE was observed, instead a strong NOE was observed between
the methyl protons and the peri-aromatic hydrogen, consistent
with the methyl being equatorially orientated and ‘trans’ to the
bridgehead proton. Treatment of 7p¢ with a catalytic quantity of
KOBut rapidly gave exclusively 7p, whereas similar treatment of
7p led to no change.
Similar treatment of the 4-chlorophenyl-a,a-dimethyl-
acetamide 3q for 5 h gave the dimethyl product 7q in a 44%
yield. Thus the cyclisation was faster than for the equivalent
4-chlorophenylacetamide 3c, but the yield of cyclised product was
no better. Notably, 7q was surprisingly unstable, decomposing at
ambient temperatures over a period of about 7 days, so the low
yield may be due to the instability of the product. Instability of
the cyclic product may be the reason for the lack of any product
7r from the cyclisation of the spirocyclopropyl amide 3r.
3f
3h
3i
3j
3k
3-Br
18
18
3
7f¢
7h
7i
7j
7k
7l
7l¢
7m
7n
7o
2-Br
7-Br
4-Phthc
4-NO2
4-Me
9-Phth
9-NO2
9-Me
8-Me
10-Me
7-Me
24d
0
1.5
75
78b
3l
3-Me
2-Me
2,3-Benzo
3,4-Benzo
1.5
1.5
1
3m
3n
3o
95
79
71
7,8-Benzo
9,10-Benzo
1.5
a Add solution of acetal over 10 min to refluxing solution of 10 equivs
of triflic acid inCHCl3. b Inseparable mixture. c Phth. = Phthalimido d In
1,2-dichloroethane
The unsubstituted phenyl-acetamide 3 gave a 60% yield of the
lactam 7 which is comparable with that obtained from both 4 and 5
(Table 1). The incorporation of electron-withdrawing substituents
again necessitated more forcing conditions and the 4-chloro 3c
and the 4-bromo 3e derivatives gave the lactams 7c and 7e,
respectively, again in comparable yields to those obtained earlier
(Table 2). The 3-bromo analogue 3f gave a good overall yield
of 71% of a mixture of 7f and 7f¢, readily separated by column
chromatography. However, the 2-bromo analogue 3h gave only
a poor yield (20%) of 7h. Less success was also obtained in the
attempted cyclisation of the 4-phthalimido-phenylacetamide 3i,
which after 3 hours gave none of the desired product and no
evidence of starting material or intermediate. We assume that
the lack of success is a consequence of the sensitivity of the
phthalimido group to the strongly acidic reaction conditions.
We have not yet found an arylamine protecting group that can
withstand the cyclisation conditions. Also notable is the lack of
success in the attempted cyclisation of 3j, which contains the
strongly electron-withdrawing 4-nitro group. However, cyclisation
of the methyl-substituted 3k, 3l and 3m all gave high yields of
cyclised product (75, 78 and 95% respectively), with the meta-
methyl 3l giving a 3 : 1 mixture of isomers that were inseparable
by column chromatography. On recording the NMR spectrum of
the mixture in C6D6, separate aromatic peaks were observed. No
large splitting of ca. 7 Hz was found for proton 7-H in the major
isomer, which was thus assigned as the 8-methyl isomer 7l. Both the
1- and 2-naphthalene acetamides (3n and 3o respectively) cyclised
rapidly and in high yield, with 3o giving a single isomer resulting
from cyclisation onto the more reactive 1-position.
The cyclisation of the a-phthalimido amide 3s, readily prepared
from phenylglycine, gave a good yield (85%) of a mixture of two
isomers in a ratio of 2.5 : 1. These products are of interest as
the benzazepine homologue 10 has been used as an intermediate
for enkephalinase inhibitors.17,18 The isomers were separated by
careful chromatography on silica. From an NMR study on the less
polar, minor isomer, irradiation of the bridgehead 10b-H proton
showed a NOE enhancement of the 6-H proton observed as a
doublet at d = 5.92 ppm, consistent with the phthalimido group
being equatorially orientated and trans to the 10b-H proton, 11a.
In addition, the aryl protons of the phthalimido group of 11a
showed up as 4 distinct multiplets, and the 13C NMR showed
three inequivalent carbonyl C signals, indicative of restricted
2.2 Cyclisation of a-substituted phenylacetamides
The effect of phenylacetyl a-substitutents on the cyclisation was
then investigated. Cyclisation of the dimethyl amide 3p (Scheme 4)
gave a readily separable 1 : 1 ratio of a mixture of isomers. From
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rotation about the C-6–N phthalimide bond. In contrast, for the
more polar, major isomer, irradiation of the signal for the 10b-H
proton showed no such enhancement and was therefore assigned
as the ‘trans’ isomer 11b, with the phthalimido group axially
orientated. Treatment of the NMR solutions of both the isomers
in CDCl3 with Et3N at ambient temperatures overnight reversed
the ratio to 2 : 1 of 11a:11b. Thus 11b is probably the kinetically
favoured product, whereas 11a is the thermodynamically more
stable isomer.
the gem-dimethyl lactam 7q, 15 was stable and therefore the low
yield is probably a consequence of steric hindrance.
Cyclisation of the 2,3-diphenylpropionamide 3v gave the 6-
benzyl isoquinolone (16b), and the 6-phenyl benzazepinones (17a)
and (17b). Initial separation on silica gave two components, the
first of which was a mixture of two products from which the 6-
phenylbenzazepinone 17a was crystallised from Et2O–petrol in a
3% yield. The remainder of this material was determined to be
a 6 : 1 mixture of 16b and 17a (32% yield). The stereochemical
assignment of 17a was based upon the observation of an NOE
enhancement at d = 7.30 (o-phenyl) and d = 7.37 (11-H proton)
on irradiation of the bridgehead 11b proton at d = 5.31, the
phenyl group being on the same face of the molecule as the
bridgehead proton. Treatment of 16b with KButO generated a
4 : 1 mixture of 16b:16a, which was readily separated by silica
column chromatography. The stereochemistry of 16a was assigned
by virtue of the chemical shift of the 10b proton is at d = 3.61,
which in 16b is at d = 4.55. For 16a, NOE enhancement was
observed at d = 6.78 for the ortho protons of the benzyl substituent
and at d = 3.09 and 3.15 for the benzylic CH2 protons when d =
3.61 was irradiated, which is all consistent with the benzyl group
positioned over the 10b proton.
The second component from the column gave a solid which
was determined to be the 6-phenylbenzazepinone 17b in a 60%
yield. Again the assignment of stereochemistry was based upon
NOE. Enhancement for the 6-H proton at d = 4.30 was observed
when bridgehead 11b proton at d = 5.19 was irradiated. This is
consistent with both protons being positioned on the same face
of the seven-membered ring. It is notable that the combined yield
of the benzazepinones 17a and 17b was higher than that of the
tetrahydro-isoquinolone 16b, suggesting that cyclisation to form
the seven-membered ring is more favoured. Treatment of 17b with
catalytic KButO in ethanol gave a 1 : 1 mixture of 17a and 17b
from which a pure sample of 17a was obtained.
We were also interested in application of our methodology to
the synthesis of analogues of potent serotonin, dopamine and
norepinephrine reuptake inhibitors, as exemplified by McN-5652,
12.9 Interest in such mixed pharmacology compounds has been
rekindled with the success of the recently marketed duloxetine (13)
for the treatment of depressive disorders.19 Triflic acid cyclisation
of the diphenylacetamide 3t gave an excellent yield of a mixture
of the 6-phenyl lactams (14a:14b) in a ratio of 2.5 : 1. The isomers
were separated by column chromatography on silica and the less
polar, major isomer crystallised from Et2O.
Despite considerable effort, the more polar isomer failed to
crystallise. From NMR studies on the less polar, major isomer,
the ortho-protons of the phenyl substituent at d = 7.12 ppm
showed relatively strong NOEs with protons 6-H and 10b-H, thus
confirming that the phenyl group is on the same face of the tricyclic
system as the bridgehead 10b hydrogen. The less polar isomer was
therefore assigned with the phenyl group axially orientated, 14a.
Heating either of 14a and 14b with 0.2 equiv. of KButO in MeOH
led to a 9 : 1 mixture of 14a:14b.
The attempted cyclisation of the triphenyl-acetamide 3u led to
the isolation of the lactam 15 in only 18% yield. However, unlike
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2.3 Cyclisation of 3-phenylpropionamides
We were pleased to note that, without taking any special pre-
cautions against racemization throughout the reaction sequence,
chiral HPLC analysis showed that the product obtained had an
ee of 97.7%. The relative stereochemistry of 10 was confirmed
by NMR. At room temperature there was restricted rotation
about the N-phthalimido group such that heating to 263K was
required to obtain good 1H and 13C NMR spectra. Further studies
showed that the energy barrier to rotation is 61 1 KJmol-1. An
NOE enhancement of the 6-H proton, a- to the N-phthalimido
group, was observed on irradiation of the 11b-H bridghead proton
consistent with the structure as shown. Interestingly, the product
obtained from cyclisation of the racemic form of 20 gave the
racemic form of 10, 10¢ in an 80% yield as a crystalline solid.
The formation of the benzazepinones 17a and 17b prompted
us to investigate the generality of applying this cyclisation to
the synthesis of benzazepinones. A limited amount of work
on the triflic acid-mediated cyclisation of N-3-phenylpropionyl-
pyrrolidinium ions to form benzazepinones has been reported for
the synthesis of dipeptide mimetics.17,18
In those patents, the iminium ion was prepared by oxidative
cleavage of an olefin to form the amido-aldehyde. We therefore
undertook a study to compare the effectiveness of iminium ion
formation from the amido-acetals and to further investigate the
scope of the cyclisation to the benzazepinones. A preliminary study
on the cyclisation of substrates containing the 3-arylpropionyl
group and the results are shown in Table 4
In general, the cyclisation to form the benzazepinones was
more rapid and higher yielding than the formation of equivalent
isoquinolones (for example 7 vs. 19a, 7c vs. 19l). In contrast to the
phenacetyl cyclisations, products were obtained from both the 2-
and 4-methoxy derivatives, compounds 18b and 18d, albeit in poor
yield. However, the yield of 19d was improved by pre-hydrolysing
the acetal of 18d in acetone/2 M HCl followed by triflic acid-
mediated cyclisation of the crude 2-hydroxypyrrolidinamide to
give 19d in a 31% overall yield. As expected, the cyclisa-
tion of amides incorporating electron-withdrawing substituents
(18h–18l) was generally slower and required prolonged heating to
ensure complete reaction. It was also noteworthy that, unlike the
isoquinolones, the benzazepinones were stable in air.
We investigated the application of this methodology to the
synthesis of the homologues of the re-uptake inhibitors derived
from 14a/b. Thus cyclisation of the 3,3-diphenylpropionamide
21 gave an excellent yield (86%) of cyclic product from which
a single, crystalline isomer 22 was obtained in 76% yield. The
stereochemistry was assigned by NMR, with a strong NOE
enhancement of the ortho-protons of the phenyl substituent
on irradiation of the bridgehead proton. In contrast to the
triphenyacetamide 3u, the cyclisation of 23 was rapid and gave
an excellent (90%) yield of 24.
We also investigated the synthesis of the previously reported
benzazepinone 10, an intermediate to enkephalinase inhibitors.17,18
From the L-phthalimdo-phenylglycine amide 20, a quantitative
yield of 10 was obtained as a glass which could not be crystallized.
As a continuation of our interest in the synthesis of poly-
phenylated amines, the cyclisation of the fluorenylacetamide 25
also gave an excellent yield (90%) of the pentacyclic lactam 26.
Table 4 Cyclisations of 3-phenylpropionamides
Comp.
R
Time/h
Comp.
Isomer
Yield (%)
18a
18b
H
2-MeO
0.5
1
19a
19b
19c
19c¢
19d
—
8
9-
11-
10
80
13
68
11
18c
18d
3-MeO
4-MeO
0.5
1
15
32%b
86
18e
18f
3,4-diMeO
3,4,5-
triMeO
4-Me
4-F
3-Br
0.5
1a
19e
19f
9,10
9,10,11
90
2.4 Formation of piperidino-tetrahydroisoquinolones and
-benzazepinones
18g
18h
18i
18j
1
6
1
6
19g
19h
19i
10
10
9
10
9-
11
10
75
77
75
78
78
9
We recently reported that the triflic acid-mediated cyclisation of
27 failed to give the piperidino-benzazocine 28.21 However, for the
six- and seven-membered analogues we found that the cyclisations
were successful, allowing the synthesis of the piperidino-tetra-
hydroisoquinolones 31 and 32 and the piperidino-benzazapin-
one 34 from the amides N-(5,5-diethoxypentyl)-2-phenyl-
acetamide 29, N-(5,5-diethoxypentyl)-2-(3,4-dimethoxyphenyl)
4-Br
19j
19k
19k¢
19l
18k
181
3-Cl
4-Cl
4
4
90
a In DCM at reflux b Overall yield from pre-hydrolysis to the hydroxypyrro-
lidine.
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acetamide 30 and N-(5,5-diethoxypentyl)-3-phenylpropionamide
33 respectively. In all cases, the cyclisations with triflic acid were
much slower than the equivalent pyrrolidino cases and lower yields
were obtained. In the case of 31, a 31% yield was obtained which
is less than the previously reported yield of 51% for the AlCl3-
mediated cyclisation of the 2-methoxypiperidinyl amide, obtained
from anodic oxidation of the amide.22
purification. Infrared spectra were run neat on a Perkin Elmer
100 FTIR 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.
General procedure for the synthesis of the arylalkyl-carboxamides
(3) and (18)
In a 100 mL round-bottomed flask connected to a drying tube,
oxalyl chloride (5 mmol, 0.35 mL) and 1–2 drops of DMF
were added to a stirred solution of the acid (5 mmol) in DCM
(40 mL). After stirring at ambient temperatures for 2 h, by which
time gas evolution had ceased, CHCl3 (10 mL) was added and
the solvent was removed by rotary evaporation under reduced
pressure. The residue was re-dissolved in 10 mL of DCM and
added, dropwise, over 10 min. to a cooled (0◦C) stirred solution of
4-aminobutyraldehyde diethylacetal (Aldrich) (5 mmol, 0.9 mL)
and dimethylethylamine (6 mmol, 0.7 mL) in Et2O (100 mL). The
reaction mixture was allowed to warm to ambient temperatures
over 2 h, when 0.2 M NaOH (30 mL) was added, after which
the white solid suspension dissolved. The reaction mixture was
transferred to a separating funnel, shaken and the lower aqueous
layer separated. The upper organic layer was then washed with
saturated NaCl solution (30 mL). The lower layer was combined
with the previous aqueous wash and the upper organic layer was
dried (K2CO3). The combined aqueous layers were back-washed
with Et2O (50 mL) and the upper organic layer separated and
added to the previously separated organic extract. The combined
organic extracts were separated and concentrated in vacuo to give
the amides as either oils, used without further purification, or as
solids, isolated by trituration with petrol (40–60◦C).
However, using this methodology it was possible to synthesise
the 3,4-dimethoxy 32, which was not possible by the anodic
oxidation method due to oxidation of the benzylic position. The
reaction to form the benzazepinone 33 was more rapid than that
for 30 but the isolated yield of 39% was poorer than for the
pyrrolidine analogue 19a. However, using the previously described
two-step procedure involving a separate acetal hydrolysis followed
by triflic acid-mediated cyclisation, yields could be improved to
49% for 30 and 86% for 33.
Conclusion
In this way the following amide was prepared:
In this paper we have further demonstrated that commercially
available 4-aminobutyraldehyde diethylacetal can be used as a
precursor to N-arylacetylpyrrolidinium ions as an alternative to
anodic oxidation. These N-arylacetyl-pyrrolidinium ion precur-
sors can be cyclised to pyrroloisoquinolinones in moderate to
high yields using either strong Lewis acids or triflic acid. As
previously reported,12 the pyrrolo-isoquinolinones are relatively
unstable in air, though stability is improved with substitution at
the 6-position. This methodology is also suitable for the synthesis
of the homologous pyrrolo-benzazepinones. From this and our
earlier publication20 the rate of cyclisation is related to the size
of the ring such that 7>6>8. The rate and yields are adversely
affected by electron-withdrawing substituents in the aryl ring,
whereas substitution on the alkyl chain between the aryl and amide
generally favours cyclisation.
N-(4,4-Diethoxybutyl)-2-phenylacetamide (3). Prepared from
the commercially available acid chloride and isolated as an oil (95%
yield). 1H NMR (400 MHz, CDCl3): d = 1.16 (t, J = 7 Hz, 6H),
1.48–1.60 (m, 4H), 3.24 (q, J = 7 Hz, 2H), 3.40–3.49 (m, 2H), 3.51
(s, 2H), 3.54–3.65 (m, 2H), 4.43 (t, J = 5 Hz, 1H), 5.57 (brs, 1H),
7.20–7.35 (m, 5): 13C NMR and distortionless enhancement with
polarisation transfer (DEPT) (75 MHz, CDCl3) d = 15.3 (CH3),
24.5 (CH2), 30.8 (CH2), 39.3 (CH2), 43.8 (CH2), 61.3 (CH2), 102.5
(CH), 127.2 (CH), 128.9 (CH), 129.4 (CH), 135.1 (C), 171.0 (C);
n
max/cm-1 2974, 2878, 1638, 1405, 1096, 1065, 719, 696.
General procedure for the synthesis of the
N-acyl-2-hydroxypyrrolidines
A solution of the appropriate N-(4,4-diethoxybutyl)acetamide
(5 mmol) in acetone (50 mL) was treated with 1M HCl (8 mL) for
15 min at ambient temperatures. The reaction mixture was basified
with an excess of 1 M NaHCO3 solution and the acetone removed
by rotary evaporation. The aqueous residue was extracted with
DCM (3 ¥ 50 mL), the combined extracts dried (K2CO3), filtered
and concentrated in vacuo to give essentially a quantitative yield
of the 2-hydroxypyrrolidine, used without further purification.
Experimental
Melting points are uncorrected. All solvents and reagents were
of commercial grade and used without purification. All evap-
orations of solvents were carried out under reduced pressure.
High-resolution mass spectrometry (HRMS) measurements were
performed with a Micromass Q-Tof 2 hybrid quadrupole time-
of-flight mass spectrometer, equipped with a Z-spray interface,
and the elemental composition was calculated using MassLynx
version 4.0. All crystalline final compounds were >97% pure, all
oils were >95% pure by NMR and HPLC immediately following
1-(2-Hydroxypyrrolidin-1-yl)-2-phenylethanone (4). Isolated
as an oil (95% yield), which gave a waxy solid on standing mpt
◦
1
46–9 C. H NMR (400 MHz, CDCl3) as a mixture of rotomers:
d = 1.78–2.15 (m, 4H), 2.97 (brs, 0.14H) 3.31–3.42 (m, 1H),
3566 | Org. Biomol. Chem., 2009, 7, 3561–3571
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3.55–3.68 (m, 2.72H), 3.80 (d, J = 15 Hz, 0.14H), 3.86 (d, J =
15 Hz, 0.14H), 4.21 (brs, 0.86H), 5.44 (brs, 0.14H), 5.66 (dd, J =
6, 3 Hz, 0.86H), 7.20–7.37 (m, 5H).
General procedure for the triflic acid-mediated cyclisation
A solution of the appropriate acetamide (2 mmol) in CHCl3
(10 mL) was added, dropwise, over 10 min. to a stirred mixture
of triflic acid (20 mmol) in CHCl3 (40 mL), heated to gentle
reflux. The reaction was monitored by taking a small aliquot of
the reaction mixture, adding a few drops of water, basifying with
K2CO3 and then analysing the CHCl3 layer on silica TLC, eluting
with EtOAc. The reaction was heated until the high running spot
had disappeared. The reaction mixture was then cooled, water was
added (10 mL) and the aqueous layer basified with K2CO3. The
organic layer was separated and the aqueous layer extracted with
DCM (2 ¥ 30 mL). The combined organic extracts were dried
(K2CO3), separated and concentrated in vacuo. The residue was
purified by column chromatography on silica, initially absorbing
the compound from a DCM solution, and then eluting with Et2O
containing appropriate amounts of MeOH up to 5%.
2-(4-Bromophenyl)-1-(2-hydroxypyrrolidin-1-yl)ethanone (4d).
◦
1
Isolated as a white solid (100% yield), mpt 110–2 C: H NMR
(300 MHz, CDCl3): d = 1.78–2.15 (m, 4H), 3.31–3.42 (m, 1H),
3.50–3.80 (m, 3H including 3.58, s, 2H), 4.20 (brs, 1H), 5.63 (dd,
J = 5.5, 2.5 Hz, 1H), 7.13 (d, J = 7 Hz, 2H), 7.44 (d, J = 7 Hz,
2H): 13C NMR and DEPT (75 MHz, CDCl3) d = 23.2 (CH2), 32.0
(CH2), 41.4 (CH2), 46.7 (CH2), 82.0 (CH), 121 (C), 130.9 (CH),
131.8 (CH), 133.1 (C), 170.9 (C).
General procedure for the synthesis of the
N-acyl-2-ethoxypyrrolidines
A
solution of the appropriate N-acyl-2-hydroxypyrrolidine
(2 mmol) in DCM (50 mL) and EtOH (0.5 mL) was stirred with 3A
molecular sieves (5 g) and TFA (0.5 mL) at ambient temperatures
for 18 h. The reaction mixture was filtered and washed with an
excess of 1 M NaHCO3 solution, then dried (K2CO3), filtered and
evaporated in vacuo to give the 2-ethoxy compounds, used without
further purification.
2,3,6,10b-Tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one
(7).
Purified by column chromatography on SiO2, eluting with Et2O
and isolated as an orange oil (60% yield); FTIR (film) nmax: 2968,
2879, 1627, 1454, 1410, 767, 736 cm-1; HRMS: theoretical mass:
(MH+) 188.1075, measured mass: (MH+) 188.1077. 1H NMR
(500 MHz, CDCl3): d = 1.75–1.86 (m, 1H), 1.87–1.97 (m, 1H),
1.97–2.06 (m, 1H), 2.55 (tt, J = 5.8, 11.6 Hz, 1H), 3.39 (dd, J =
8.7, 7.7 Hz, 1H), 3.44 (d, J = 18.1 Hz, 1H), 3.52 (d, J = 18.1 Hz,
1H) 3.59 (t, J = 11.2 Hz, 1H), 4.50–4.56 (m, 1H), 7.04–7.15
(m, 2H), 7.15–7.21 (m, 2H); 13C NMR and DEPT (75 MHz,
CDCl3) d = 23.2 (CH2), 31.3 (CH2), 38.7 (CH2), 59.6 (CH), 124.0
(CH), 126.8 (CH), 127.2 (CH), 127.6 (CH), 133.0 (C), 136.2 (C),
167.5 (C).
1-(2-Ethoxypyrrolidin-1-yl)-2-phenylethanone (5). Isolated as
1
an oil (75% yield). H NMR (400 MHz, CDCl3) as a mixture
of rotomers: d = 1.16 (t, J = 7.2 Hz, 1.5H), 1.27 (t, J = 7.2 Hz,
1.5H), 1.64–2.21 (m, 4H), 3.31–3.72 (m, 6H), 5.08 (d, J = 4.8,
0.5H), 5.55 (d, J = 4.8, 0.5H), 7.12–7.35 (m, 5H).
2-(4-Chlorophenyl)-1-(2-ethoxypyrrolidin-1-yl)ethanone
(5c).
1
Isolated as an oil (85% yield). H NMR (300 MHz, CDCl3) as a
mixture of rotomers: d = 1.13 (t, J = 7 Hz, 1.5H), 1.22 (t, J =
7 Hz, 1.5H), 1.60–2.20 (m, 4H), 3.22–3.76 (m, 6H), 5.05 (d, J =
4 Hz, 0.5H), 5.51 (d, J = 4 Hz, 0.5H), 7.12–7.29 (m, 4H); 13C
NMR and DEPT (75 MHz, CDCl3) d = 15.3 (CH3), 15.4 (CH3),
21.1 (CH2), 23.1 (CH2), 31.5 (CH2), 31.9 (CH2), 40.3 (CH2), 41.3
(CH2), 45.9 (CH2), 46.4 (CH2), 62.1 (CH2), 64.6 (CH2), 86.0 (CH),
87.6 (CH), 128.6 (CH), 128.7 (CH), 130.6 (CH), 130.7 (CH),
132.6 (C), 132.7 (C), 133.1 (C), 133.7 (C), 170.3 (C), 170.6 (C).
2-((6s,10bR/6R10bS)-5-Oxo-1,2,3,6,10b-hexahydro-pyrrolo[2,
1-a]isoquinolin-6-yl)isoindole-1,3-dione (11a). The less polar iso-
mer was isolated as a pale yellow solid from a SiO2 column
purification, eluting with 1 : 1 Et2O–petrol (24% yield) mpt 249–
51◦C (Et2O). Alternatively treatment of the crude product with
Et3N (5 equiv.) in DCM, concentration and column as before
gave 11a (57% yield). HRMS theoretical mass: (MH+) 332.1155,
1
measured mass: (MH+) 332.1163. H NMR (500 MHz, 298K,
CDCl3): d = 2.01–2.25 (m, 3H), 2.67–2.77 (m, 1H), 3.58–3.67 (dd,
J = 8.1, 11.7 Hz, 1H), 3.70–3.77 (dt, J = 8.2, 11.0 Hz, 1H), 4.69–
4.73 (brs, 1H), 5.92 (d, J = 1.1 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H),
7.24–7.29 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.72–7.80 (m, 2H),
7.85 (dd, J = 1.7, 5.8 Hz, 1H), 7.95 (dd, J = 1.5, 5.8 Hz, 1H);
13C NMR and DEPT (125.8 MHz, CDCl3) d = 23.3 (CH2), 31.5
(CH2), 45.3 (CH2), 52.5 (CH), 58.8 (CH), 123.8 (CH), 123.8 (C),
124.1 (CH), 124.5 (CH), 127.8 (CH), 128.0 (CH), 131.6 (C), 132.2
(C), 134.2 (CH), 134.3 (CH), 134.7 (C), 162.9 (C), 167.1 (C), 168.6
(C); nmax/cm-1 1713, 1655, 1441, 1386, 904, 763, 742, 725, 697.
2-Phenyl-1-(1¢-phenylacetyl-2,3,4,5,4¢,5¢-hexahydro-1¢H-[2,3¢]-
bipyrrol-1-yl)ethanone (9). The amide (5) (1.2 g, 5 mmol) was
stirred with conc. H2SO4 (5 mL) according to the literature
procedure.13 The reaction mixture was carefully treated with ice
(~20 g) and basified with solid K2CO3. The product was extracted
into DCM (2 ¥ 50 mL), dried (K2CO3), filtered, concentrated in
vacuo and purified by column chromatography on SiO2, eluting
with EtOAc to give a white crystalline solid (0.79 g, 85% yield). A
small sample was recrystallised from EtOAc to yield crystals for
X-ray analysis, mpt 104–8◦C. HRMS theoretical mass: 375.2072,
measured mass: 375.2075. 1H NMR (400 MHz, CDCl3) as a
mixture of rotomers: d = 1.65–2.05 (m, 4H), 2.46–2.72 (m, 2H),
3.40–3.70 (m, 6H), 3.75–3.98 (m, 2H), 4.41 (d, J = 8 Hz, 0.24H),
4.49 (d, J = 8 Hz, 0.16H), 4.77 (dd, J = 10, 8 Hz, 0.6H), 6.06
(dd, J = 3, 3 Hz, 0.4H), 6.15 (d, J = 1 Hz, 0.3H), 6.66 (dd, J =
3.5, 2 Hz, 0.18H), 6.83 (d, J = 1 Hz, 0.12H), 7.09 (d, J = 7 Hz,
0.75H), 7.12–7.48 (m, 9.25H). Chiral HPLC was run on a Chiracel
OJ 4.6 ¥ 250 mm column with 10 mm particle size, eluting with
heptane–EtOH 7 : 3 at a flow rate of 1 mL min-1. Retention times
of 28 and 45 min. were obtained for each enantiomer.
2-((6R,10bR/6S10bS)-5-Oxo-1,2,3,6,10b-hexahydro-pyrrolo[2,
1-a]isoquinolin-6-yl)isoindole-1,3-dione (11b). The more polar
isomer was isolated as a pale yellow solid from a SiO2 column
purification, eluting with 3 : 1 Et2O–petrol (61% yield), mpt 210–
4◦C. HRMS theoretical mass: (MH+) 332.1155, measured mass:
1
(MH+) 332.1164. H NMR (500 MHz, 298K, CDCl3): d = 1.87
(tt, J = 8.0, 11.8 Hz, 1-H), 2.03–2.22 (m, 2,2-H), 2.71 (tt, J =
6.5, 12 Hz, 1-H), 3.69–3.81 (m, 4,4-H), 5.10 (dd, J = 5.4, 11.8 Hz,
10b-H), 5.95 (d, J = 1.9 Hz, 6-H), 7.21–7.37 (m, 4H), 7.67 (dd, J =
5.5, 3 Hz, 2H), 7.78 (dd, J = 5.5, 3 Hz, 2H): 13C NMR and DEPT
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(125.8 MHz, CDCl3) d = 22.2 (2-C), 32.1 (1-C), 45.3 (3-C), 51.0
(6-C), 60.1 (10b-C), 123.5 (CH), 124.8 (CH), 128.2 (CH), 128.6
(CH), 128.6 (CH), 131.7 (C), 132.0 (C), 134.3 (CH), 136.9 (C),
163.3 (C), 167.5 (C) nmax/cm-1 1709, 1657, 1387, 1111, 893, 773,
717.
1H), 7.08 (t, J = 7.0 Hz, 2¢, 4¢-H), 7.13 (t, J = 7.0 Hz, 3¢-H), 7.14
(t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H: 13C NMR and DEPT
(125.8 MHz, CDCl3) d = 22.5 (2-C), 31.8 (1-C), 40.7 (1¢-C), 44.7
(3-C), 50.5 (6-C), 58.7 (10b-C), 124.0 (CH), 126.5 (CH), 126.7
(CH), 127.3 (CH), 127.8 (CH), 127.8 (CH), 129.6 (CH), 135.5 (C),
136.0 (C), 137.4 (C), 169.4 (C);nmax/cm-1 1712, 1655, 1386, 1109,
904, 725.
(6S, 10bS)/(6R, 10bR)-6-Phenyl-2,3,6,10b-tetrahydro-1H-py-
rrolo[2,1-a]isoquinolin-5-one (14a). Isolated as pale yellow solid
(71% yield), mpt 126–8◦C (lit. 120◦C22). HRMS theoretical mass:
263.1305, measured mass: 263.1305. 1H NMR (500 MHz, CDCl3):
d = 1.86–1.97 (m, 2H), 2.06–2.15 (m, 1H), 2.58–2.67 (m, 1H),
3.51–3.60 (m, 1H), 3.60–3.65 (m, 1H), 4.53 (dd, J = 5.7, 10.1 Hz,
H-10b), 4.92 (s, H-6), 7.12 (dd, J = 7.3, 0.5 Hz, 2H), 7.17–7.31
(m, 5H), 7.31–7.37 (m, 2H): 13C NMR and DEPT (125.8 MHz,
CDCl3) d = 23.0 (2-CH2), 31.7 (1-CH2), 45.3 (3-CH2), 54.4 (6-CH),
59.0 (10b-CH), 124.5 (CH), 127.1 (CH), 127.4 (CH), 127.5 (CH),
128.2 (CH), 128.6 (CH), 128.7 (CH), 135.9 (C), 137.1 (C), 138.1
(C), 168.6 (C). NOE irradiation of ortho-CH of phenyl substituent
enhanced both 10b-H and 6-H.
(6S, 10bR)/(6R, 10bS)-6-Benzyl-2,3,6,10b-tetrahydro-1H-py-
rrolo[2,1-a]isoquinolin-5-one (16b). Isolated from the cyclisation
of 3v, purified on SiO2 and eluting with Et2O to isolate the less
polar fraction, from which 17a was crystallised from Et2O–petrol.
Concentration of the mother liquors gave the title compound as an
oil (29% yield, 90% pure by NMR, the remainder being 17a); MS
1
theoretical mass: 277.1461, measured mass: 277.1465; H NMR
(300 MHz, CDCl3): d = 1.56–1.72 (m, 1H), 1.86–2.07 (m, 2H),
2.41 (m, 0.1H), 2.49 (ddt, 0.9H), 2.65 (dt, 0.1H), 2.98 (dd, 0.1H),
3.37–3.89 (m, 4.8 H), 4.46–4.57 (m, 0.9H), 5.29 (t, 0.1H), 7.10–
7.39 (m, 9H); 13C NMR and DEPT (75 MHz, CDCl3) d = 23.3
(CH2), 31.2 (CH2), 33.8 (CH2), 44.9 (CH2), 46.2 (CH), 59.0 (CH),
123.9 (CH), 125.8 (CH), 126.0 (CH), 126.6 (CH), 127.5 (CH),
128.2 (CH), 128.9 (CH), 129.9 (C), 136.2 (C), 137.1 (C) 139.9 (C),
169.0 (C).
(6S, 10bR)/(6R, 10bS)-6-Phenyl-2,3,6,10b-tetrahydro-1H-py-
rrolo[2,1-a]isoquinolin-5-one (14b). Isolated as a foam (29%
yield). HRMS theoretical mass: 263.1305, measured mass:
1
263.1306. H NMR (300 MHz, CDCl3): d = 1.97–2.32 (m, 3H),
2.66–2.80 (m, 1H), 3.58 (q, J = 9.5 Hz, 1H), 3.77 (dd, J = 12, 7 Hz,
1H), 4.63–4.77 (m, 2H including 4.67 s, 1H), 6.65 (d, J = 8 Hz,
1H), 7.12–7.56 (m, 8H): 13C NMR and DEPT (75 MHz, CDCl3)
d = 23.3 (CH2), 31.5 (CH2), 45.3 (CH2), 53.8 (CH), 58.9 (CH),
123.7 (CH), 126.8 (CH), 127.3 (CH), 127.5 (CH), 128.5 (CH),
128.9 (CH), 131.1 (CH), 136.8 (C), 137.4 (C), 137.7 (C), 168.2 (C).
(6S,11bR/6R,11bS)-6-Phenyl-1,2,3,6,7,11b-hexahydro-benzo-
[c]pyrrolo[1,2-a]azepin-5-one (17a). Isolated from the cyclisation
of 3v, purified on SiO2 and eluting with Et2O to isolate the
less polar fraction. From this, 17a was crystallised from Et2O–
petrol (3% yield), mpt 125–7◦C. MS theoretical mass: 277.1461,
measured mass: 277.1466; 1H NMR (500 MHz, CDCl3): d =
1.90–2.10 (m, 2H), 2.41 (quintet, J = 7.2 Hz, 1H), 2.65 (quintet,
J = 6.3 Hz, 1H), 2.99 (dd, J = 14.7, 5.4 Hz, 1H), 3.53 (dd, J =
12.9, 14.6 Hz, 1H), 3.72 (t, J = 6.8 Hz, 1H), 3.81 (dd, J = 12.9,
5.4 Hz, 1H), 5.31 (dd, J = 7.0, 6.2 Hz, 1H), 7.26–7.33 (m, 5H),
7.35–7.38 (m, 4H). NOE irradiation of 1-H at d = 5.31 showed
an enhancement of the ortho-phenyls at d = 7.30 and 7.37.13C
NMR and DEPT (125 MHz, CDCl3) d = 22.5 (CH2), 29.9 (CH2),
38.2 (CH2), 48.5 (CH2), 53.6 (CH), 56.1 (CH), 123.4 (CH), 126.7
(CH)126.8 (CH), 127.6 (CH), 128.2 (CH), 128.7 (CH), 129.1 (CH),
139.1 (C), 139.5 (C), 142.8 (C), 170.7 (C). HRMS theoretical mass:
277.14612, measured mass: 277.14580; nmax/cm-1 1610, 1599, 1583,
1421, 776, 748, 703, 658.
6,6-Diphenyl-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]iso-quino-
lin-5-one (15). Isolated as white solid (18% yield), mpt 176–
9◦C. HRMS theoretical mass: 339.1618, measured mass: 339.1611;
1H NMR (300 MHz, CDCl3): d = 1.78–2.19 (m, 3H), 2.53–2.65
(m, 1H), 3.56–3.83 (m, 2H), 4.09 (dd, J = 10, 6 Hz, 1H), 6.62 (d,
J = 8 Hz, 1H), 6.66–6.91 (m, 2H), 7.08 (dd, J = 7, 3 Hz, 2H),
7.15–7.40 (m, 9H): 13C NMR and DEPT (75 MHz, CDCl3) d =
23.0 (CH2), 31.4 (CH2), 45.8 (CH2), 57.8 (CH), 64.4 (C), 123.8
(CH), 126.7 (CH), 127.0 (CH), 127.4 (CH), 128.3 (CH), 129.0
(CH), 129.7 (CH), 131.0 (CH), 138.2 (C), 139.3 (C), 141.7 (C),
143.5 (C), 170.2 (C). nmax/cm-1 1649, 1446, 1413, 752, 727, 704,
676.
(6R, 10bR)/(6S, 10bS)-6-Benzyl-2,3,6,10b-tetrahydro-1H-py-
rrolo[2,1-a]isoquinolin-5-one (16a). Isolated from the cyclisation
of 3v, purified on SiO2 and eluting with Et2O to isolate the less
polar fraction. From this, 17a was crystallised from Et2O–petrol.
Concentration of the mother liquors gave an oil (1.09 g) which
was treated with KButO (0.1 g) in Et2O (20 mL) at ambient
temperatures for 4 days. The reaction mixture was then acidified
with 2 M HCl and the organic layer separated, dried (K2CO3) and
concentrated in vacuo. Purification by column chromatography on
SiO2, eluting with Et2O + 25% petrol gave a more polar fraction,
which on concentration afforded the title compound as an oil (7%
yield). MS theoretical mass: 277.1461, measured mass: 277.1463;
1H NMR (500 MHz, CDCl3): d = 1.57–1.67 (m, 1-H), 1.71–1.82
(m 2-H), 1.95–2.03 (m 2-H), 2.39 (tt, J = 5.9, 11.7 Hz, 1-H), 3.09
(dd, J = 12.9, 4.8 Hz, 1¢-H), 3.15 (dd, J = 12.9, 4.8 Hz, 1¢-H), 3.61
(dd, J = 11.1, 5.6 Hz, 10b-H), 3.80 (t, J = 5.5 Hz, 6-H), 6.78 (d,
J = 7.0 Hz, 5¢,5¢-H), 6.84 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 7.4 Hz,
(6S,11bS/6R,11bR)-6-Phenyl-1,2,3,6,7,11b-hexahydro-benzo-
[c]pyrrolo[1,2-a]azepin-5-one (17b). Isolated from the cyclisation
of 3v, purified on SiO2 and eluting with Et2O + 1% MeOH to
isolate the more polar fraction, which on concentration gave an
oil which gave the title compound as a solid from Et2O (47% yield)
mpt 150–2◦C. MS theoretical mass: 277.1461, measured mass:
1
277.1458; H NMR (500 MHz, CDCl3): d = 1.88–1.99 (m, 1H),
2.01–2.09 (m, 1H), 2.48–2.52 (m, 2H), 3.13 (d,d J = 15.4, 7.4 Hz,
1H), 3.48–3.58 (m, 2H), 4.02 (dddd, J = 12.0, 7.7, 3.5, 0.8 Hz,
1H), 4.30 (dd, J = 7.3, 3.6 Hz, 1H), 5.19 (dd, J = 8.2, 6.9 Hz, 1H),
6.77 (ddd, J = 7.5, 1.5, 0.4 Hz, 1H), 6.90 (dd, J = 7.6, 1.3 Hz, 2H),
7.10 (tdd, J = 7.4, 1.3, 0.4 Hz, 1H), 7.14–7.25 (m, 4H), 7.34 (d,
1H, J = 7.9 Hz): NOE irradiation of 1-H at d = 5.19 showed an
enhancement of the 11-H proton at d = 7.34 and the 6-H proton
at d = 4.30: 13C NMR and DEPT (75 MHz, CDCl3) d = 22.9
(CH2), 31.7 (CH2), 37.6 (CH2), 48.2 (CH2), 50.4 (CH2), 58.1 (CH),
3568 | Org. Biomol. Chem., 2009, 7, 3561–3571
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124.8 (CH), 126.5 (CH), 126.5 (CH), 127.5 (CH), 128.0 (CH),
128.5 (CH), 130.5 (CH), 137.7 (C), 138.2 (C), 141.0 (C), 171.8 (C)
H-9), 7.52–7.25 (m, 3H), 7.82 (d, J = 6.3 Hz, 1H, 1-H); 13C NMR
(125.8 MHz, CDCl3 at 263 K) d = 23.1, 31.9, 35.0, 48.1. 52.1, 58.6,
123.4, 123.5, 125.4, 127.1, 127.9, 130.1, 131.5, 131.9, 134.1, 134.3,
1
136.4, 137.4, 167.2, 167.6, 168.2. H NMR (500 MHz, CDCl3 at
General procedure for the aluminium chloride-mediated synthesis
333 K): d = 1.87–1.98 (m, 1H), 1.99–2.07 (m, 1H), 2.51–2.60 (m,
2H), 3.41 (dd, J = 15.8, 4.5 Hz, 1H), 3.45–3.53 (m, 1H), 3.84
(dd, J = 16.2, 8.9 Hz, 1H), 3.88–3.94 (m, 1H), 5.10 (dd, J = 7.8,
8.9 Hz, 1H), 5.39 (dd, J = 8.8, 3.7 Hz, 1H), 7.07 (d, J = 6.8 Hz,
1H), 7.15 (t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.29 (d,
J = 7.8 Hz, 1H), 7.63–7.67 (m, 2H), 7.76–7,78 (m, 2H). Chiral
HPLC was run on a Chiracel OJ 4.6 ¥ 250 mm column with 10 mm
particle size, eluting with heptane–EtOH 1 : 1 at a flow rate of
1 mL/min. Retention times of 8.1 and 11.4 min. were obtained for
each enantiomer.
of the 2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-ones
To a stirred solution of the phenyl acetamide (2 mmol) in CHCl3
(30 mL) was added AlCl3 (6 mmol) at ambient temperature. The
reaction was monitored by taking a small aliquot of the reaction
mixture, adding a few drops of water, basifying with K2CO3
and then analysing the CHCl3 layer on silica TLC, eluting with
EtOAc. The reaction was stirred until the high running spot had
disappeared. The reaction mixture was then cooled, water was
added (2 mL) and the aqueous layer basified, then saturated with
K2CO3. The organic layer was separated and the solid residue
extracted with DCM (2 ¥ 30 mL). The combined organic extracts
were dried (K2CO3), separated and concentrated in vacuo. The
residue was purified by column chromatography on silica, initially
absorbing the compound from a DCM solution, and then eluting
with Et2O containing appropriate amounts of MeOH up to 5%.
N-(4,4-Diethoxybutyl)-3,3-diphenylpropionamide (21). Iso-
lated◦ as an oil which solidified on standing (95% yield), mpt
61–4 C. 1H NMR (300 MHz, CDCl3): d = 1.18 (t, J = 7 Hz, 6H),
1.31–1.49 (m, 4H), 2.86 (d, J = 8 Hz, 2H), 3.10 (q, J = 6 Hz, 2H),
3.39–3.50 (m, 2H), 3.52–3.75 (m, 2H), 4.36 (t, J = 5 Hz, 1H),
4.56 (t, J = 8 Hz, 1H), 5.56 (brs, 1H), 7.14–7.31 (m, 10H); 13C
NMR and DEPT (75 MHz, CDCl3) d = 15.4 (CH3), 24.5 (CH2),
30.8 (CH2), 39.1 (CH2), 43.5 (CH2), 47.5 (CH), 102.6 (CH), 126.5
(CH), 127.8 (CH), 128.6 (CH), 143.7 (C), 171.0 (C).
N-(4,4-Diethoxybutyl)-3-phenylpropionamide (18a). Isolated
1
as an oil (100% yield). H NMR (300 MHz, CDCl3): d = 1.18
(t, J = 7.1 Hz, 6H), 1.44–1.62 (m, 4H), 2.43 (t, J = 7.5 Hz, 2H),
2.93 (t, J = 7.5 Hz, 2H), 3.20 (q, J = 6.3 Hz, 2H), 3.40–3.52 (m,
2H), 3.55–3.67 (m, 2H), 4.42 (t, J = 5 Hz, 1H). 5.73 (brs, 1H),
7.12- 7.30 (m, 5H); 13C NMR and DEPT (75 MHz, CDCl3) d =
15.3 (CH3), 24.5 (CH2), 31.0 (CH2), 31.8 (CH2), 38.5 (CH2), 39.2
(CH2), 61.4 (CH2), 102.6 (CH), 126.2 (CH), 128.3 (CH), 128.5
(CH), 140.9 (CH), 172.1 (C); nmax/cm-1 2974, 2928, 2874, 1643,
1589, 1453, 1373, 1125, 1058, 994, 749.
7-Phenyl-1,2,3,6,7,11b-hexahydro-benzo[c]pyrrolo[1,2-a]azepin-
5-one (22). Isolated as a solid (76% yield) mpt 118–9◦C
(Et2O/–petrol), HRMS theoretical mass: 277.1461, measured
mass: 277.1467. 1H NMR (500 MHz, CDCl3): d = 1.79–1.89 (m,
H-2), 1.92–2.02 (m, H-2), 2.27–2.36 (m, H-1), 2.50–2.58 (m, H-2),
2.83 (dd, J = 5, 15.1 Hz, H-6), 3.37–3.50 (m, H-3, H-6), 3.72–3.79
(m, H-3), 4.49 (dd, J = 5, 10.5 Hz, H-7), 7.08 (d, J = 8.3 Hz, 1H),
7.12 (dd, J = 1.4, 8.4 Hz, 2H), 7.16–7.23 (m,3H), 7.24–7.31 (m,
3H); 13C NMR (125.8 MHz, CDCl3) d = 23.1 (CH2), 30.4 (CH2),
42.6 (CH2), 46.0 (CH), 46.5 (CH2), 57.6 (CH), 124.9 (CH), 126.5
(CH), 127.5 (CH), 127.9 (CH), 128.7 (CH), 132.5 (CH), 137.4
(C), 141.8 (C), 145.7 (C), 170.3 (C); nmax/cm-1 1636, 1448, 1430,
1304, 755, 701.
1,2,3,6,7,11b - hexahydro - benzo[c]pyrrolo[1,2 - a]azepin - 5 - one
(19a). Isolated as an oil (80% yield), HRMS theoretical mass:
201.1148, measured mass: 201.1154. 1H NMR (300 MHz, CDCl3):
d = 1.76–2.02 (m, 2H), 2.22–2.55 (m, 3H), 2.78–2.95 (m, 2H), 3.15–
3.29 (m, 1H), 3.36–3.50 (m, 1H), 3.70–3.81 (m, 1H), 5.04 (t, J =
7.7 Hz, 1H,), 7.19–2.28 (m, 5H); 13C NMR and DEPT (75 MHz,
CDCl3) d = 22.8 (CH2), 29.1 (CH2), 30.6 (CH2), 35.9 (CH2), 48.1
(CH2), 56.9 (CH), 124.4 (CH), 126.5 (CH), 128.2 (CH), 128.9
(CH), 138.2 (C), 140.8 (C), 170.7 (C); nmax/cm-1 1596, 1446, 1401,
1306, 754, 696.
N-(4,4-Diethoxybutyl)-3,3,3-triphenylpropionamide (23). Iso-
lated as a white solid (96% yield), mpt 110–2◦C (Et2O–petrol).
1H NMR (300 MHz, CDCl3): d = 1,17 (t, J = 7 Hz, 6H), 1.25–
1.40 (m, 2H), 2.93 (q, J = 6 Hz, 2H), 3.35–3.48 (m, 2H), 3.50–3.64
(m, 4H including 3.54, s, 2H), 4.33 (t, J = 5.5 Hz, 1H), 4.85 (brs,
1H), 7.10–7.32 (m, 15H); 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.4 (CH3), 24.2 (CH2), 30.8 (CH2), 39.2 (CH2), 48.8 (CH2),
56.2 (C), 61.1 (CH2), 102.5 (CH), 126.5 (CH), 128.1 (CH), 129.3
(CH), 146.3 (C), 170.5 (C).
(S)-N-(4,4-Diethoxybutyl)-2-[4-(1,3-dioxo-1,3-dihydroisoindol-
2-yl)-3-phenylpropionamide (20). Isolated as a white solid (91%
yield), mpt 78–80◦C. (Et2O–petrol). 1H NMR (300 MHz, CDCl3):
d = 1.11 (t, J = 7 Hz, 3H), 1.13 (t, J = 7 Hz, 3H), 1.51–1.67 (m,
4H), 3.18–3.62 (m, 8H), 4.44 (t, J = 5 Hz, 1H), 5.07 (dd, J = 6,
10 Hz, 1H), 6.40 (brs, 1H), 7.06–7.20 (m, 5H), 7.63–7.71 (m, 2H),
7.71–7.79 (m, 2H); nmax/cm-1 2973, 1712, 1642, 1545, 1380, 1103,
1065, 874, 721, 707.
7,7-Diphenyl-1,2,3,6,7,11b-hexahydro-benzo[c]pyrrolo[1,2-
a]azepin-5-one (24)
2-((6S,11bS)-5-Oxo-2,3,5,6,7,11b-hexahydro-1H-benzo[c]pyr-
Isolated as a white solid (90% yield), mpt 153–6◦C (Et2O–petrol).
HRMS theoretical mass: 353.1774, measured mass: 353.1785. 1H
NMR (300 MHz, CDCl3): d = 1.60–1.79 (m, 1H), 1.83–1.97 (m,
1H), 2.21–2.40 (m, 1H), 2.45–2.59 (m, 1H), 3.00–3.13 (m, 1H), 3.40
(d, J = 15 Hz, 1H), 3.84 (brt, J = 9 Hz, 1H), 3.92 (d, J = 15 Hz,
1H), 4.87 (dt, J = 2.7, 7 Hz, 1H), 6.64 (d, J = 7 Hz, 1H), 7.01–7.41
(m, 13H); 13C NMR and DEPT (75 MHz, CDCl3) d = 22.9 (CH2),
33.7 (CH2), 46.6 (CH2), 49.2 (CH2), 54.8 (C), 59.4 (CH2), 126.6
(CH), 126.7 (CH), 126.7 (CH), 126.9 (CH), 127.0 (CH), 127.7
rolo[1,2-a]azepin-6-yl)-isoindole-1,3-dione (10). Isolated as
a
1
glass (70% yield); H NMR (500 MHz, CDCl3 at 263 K): d =
1.85–1.97 (m, 1H, H-2), 2.01–2.19 (m, 1H, H-2), 2.48–2.59 (m,
2H, H-1,1), 3.41 (dd, J = 16.2, 3.9 Hz, 1H, H-7), 3.43–3.51 (m,
1H, H-3), 3.76 (dd, J = 16.2, 8.7 Hz, 1H, H-7), 3.88–3.95 (m, 1H,
H-8), 5.19 (t, J = 7.2 Hz, 1H, H-11b), 5.38 (dd, J = 8.7, 3.9 Hz,
1H, H-6), 7.05 (d, J = 7.5 Hz, 1H, H-8), 7.17 (t, J = 7.5 Hz, 1H,
H-9), 7.26 (t, J = 7.5 Hz, 1H, H-10), 7.32 (d, J = 7.5 Hz, 1H,
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(CH), 128.3 (CH), 128.5 (CH), 129.7 (CH), 133.1 (CH), 137.9 (C),
144.8 (C), 145.2 (C), 148.2 (C), 170.3 (C); nmax/cm-1 1650, 1430,
761, 727, 740, 700, 678.
36.4 (CH2), 43.9 (CH2), 61.7 (CH). 125.5 (CH), 126.7 (CH), 127.4
(CH), 127.6 (CH), 130.3 (C), 134.1 (C), 166.7 (C).
9,10-Dimethoxy-1,2,3,4,7,11b-hexahydro-benzo[a]-quinolizin-
6-one (32). Isolated as a pale yellow solid (60% yield) mpt 103–
6◦C (Et2O–petrol), HRMS theoretical mass: 261.1359, measured
mass: 261.1362. 1H NMR (500 MHz, CDCl3): d = 1.40–1.58 (m,
2H), 1.68–1.76 (m, 2H), 1.97 (dd, J = 12.8, 1.7 Hz, 1H), 2.07 (dd,
J = 12.1, 1.2 Hz, 1H), 2.59 (dt, J = 10.5, 2.5 Hz, 1H), 3.52 (d,
J = 21.0 Hz, 1H), 3.60 (d, J = 21.0 Hz, 1H), 3.85 (s, 6H), 4.34
(dd, J = 11.8, 1.7 Hz, 1H), 4.89 (dt, J = 13.0, 2.3 Hz, 1H), 6.50 (s,
1H), 6.62 (s, 1H); 13C NMR and DEPT (125.8 MHz, CDCl3) d =
25.08 (CH2), 25.2 (CH2), 34.6 (CH2), 36.6 (CH2), 43.8 (CH2), 56.0
(CH3), 56.1 (CH3), 61.5 (CH), 108.2 (CH), 109.8 (CH), 122.3 (C),
126.0 (C), 148.1 (C), 148.6 (C), 166.7 (C); nmax/cm-1 2937, 2847,
1641, 1521, 1464, 1321, 1269, 1246, 1227, 1119, 1015, 998, 846,
761.
N-(4,4-Diethoxybutyl)-2-(9H-fluoren-9-yl)-acetamide
(25).
Isolated as a white solid (93% yield), mpt 82–6◦C (Et2O–petrol).
1H NMR (300 MHz, CDCl3): d = 1.18 (t, J = 7 Hz, 6H),
1.48–1.67 (m, 4H), 2.58 (d, J = 7.4 Hz, 2H), 3.33 (q, J = 6 Hz,
2H), 3.40–3.51 (m, 2H), 3.53–3.75 (m, 2H), 4.46 (t, J = 5.2 Hz,
1H), 4.51 (t, J = 7.4 Hz, 1H), 5.55 (brs, 1H), 7.29 (t, J = 7.4 Hz,
2H), 7.37 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 7.3 Hz, 2H), 7.75
(d, J = 7.4 Hz, 2H), 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.3 (CH3), 24.6 (CH2), 31.0 (CH2), 39.4 (CH2), 41.0 (CH2),
44.0 (CH), 61.4 (CH2), 47.5 (CH), 102.6 (CH), 119.9 (CH), 124.5
(CH), 127.2 (CH), 127.4 (CH), 140.7 (C), 146.5 (C), 171.1 (C).
1,3,4,5,6,14b-Hexahydro-fluoreno[1,9-cd]-pyrrolo[3,4-a]azepine-
2-one (26). Isolated as a white solid (90% yield) mpt 156–
8◦C. HRMS theoretical mass: 275.1305, measured mass:
N-(5,5-Diethoxypentyl)-3-phenylpropionamide (33). Isolated
1
1
as an oil (94% yield). H NMR (300 MHz, CDCl3): d = 1.17
275.1305. H NMR (300 MHz, CDCl3): d = 1.82–2.08 (m, 4H),
(t, J = 7 Hz, 6H), 1.21–1.31 (m, 2H), 1.33–1.46 (m, 2H), 1.48–1.59
(m, 2H), 2.42 (t, J = 7.5 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 3.17
(q, J = 6.5 Hz, 2H), 3.36–3.49 (m, 2H), 3.50–3.64 (m, 2H), 4.42 (t,
J = 5.5 Hz, 1H), 5.62 (brs, 1H), 7.12–7.28 (m, 5H), 13C NMR and
DEPT (75 MHz, CDCl3) d = 15.4 (CH3), 22.0 (CH2), 29.3 (CH2),
31.8 (CH2), 33.3 (CH2), 38.5 (CH2), 39.4 (CH2), 61.1 (CH2), 102.8
(CH), 126.2 (CH), 128.3 (CH), 128.5 (CH), 140.9 (C), 172.0 (C).
2.23–2.40 (m, 2H), 2.72 (t, J = 13 Hz, 1H), 2.75–2.89 (m, 1H),
3.24 (dd, J = 13, 1.4 Hz, 1H), 3.40–3.52 (m, 1H), 4.05–4.22 (m,
2H), 5.00 (t, J = 8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.28–7.44
(m, 3H), 7.57 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.74
(d, J = 6.7 Hz, 1H); 13C NMR and DEPT (75 MHz, CDCl3) d =
22.7 (CH2), 34.5 (CH2), 38.3 (CH2), 44.1 (CH), 48.0 (CH2), 60.3
(CH), 118.8 (CH), 120.2 (CH), 123.7 (CH), 124.1 (CH), 127.4
(CH), 127.5 (CH), 128.0 (CH), 135.6 (C), 140.0 (C), 140.8 (C),
144.3 (C), 145.7 (C), 174.1 (C).
1,3,4,7,8,12b-Hexahydro-2H-pyrido[2,1-a][2]benzazepin-6-one
(34). N-(5,5-Diethoxypentyl)-3-phenylpropionamide (0.8 g) was
dissolved in acetone (50 mL) and 5 mL of 2 M HCl added. After
standing at ambient temperatures for 30 min., an excess of solid
K2CO3 was added and the acetone removed by rotary evaporation.
The residue was extracted with DCM (3 ¥ 50 mL), dried (K2CO3)
and the solvent removed by rotary evaporation to give a clear oil
(0.7 g). This oil was dissolved in CHCl3 and cyclised with triflic
acid (2.3 mL) by the previously described procedure to give the
product as an oil which crystallised on trituration with 1 : 1 Et2O–
petrol (86% yield), mpt 91–3◦C. 1H NMR (500 MHz, CDCl3): d =
1.58–1.96 (m, 5H), 2.10–2.20 (m, 1H), 2.71–2.83 (m, 1H), 2.89–
3.04 (m, 2H), 3.12–3.25 (m, 1H), 3.49–3.57 (m, 1H), 3.60–3.75 (m,
1H), 4.90 (dd, J = 4.4, 7.9 Hz, 1H), 7.06–7.30 (m, 4H); 13C NMR
and DEPT (125.8 MHz, CDCl3) d = 23.3 (CH2), 24.7 (CH2), 29.4
(CH2), 30.4 (CH2), 36.2 (CH2), 42.6 (CH2), 59.8 (CH), 126.2 (CH),
127.5 (CH), 127.8 (CH), 129.9 (CH), 138.6 (C), 139.4 (C), 172.7
(C).
N-(5,5-Diethoxypentyl)-2-phenylacetamide (29). Isolated as
1
an oil (98% yield). H NMR (300 MHz, CDCl3): d = 1.16 (t,
J = 7 Hz, 6H), 1.21–1.31 (m, 2H), 1.33–1.46 (m, 2H), 1.48–1.59
(m, 2H), 3.17 (q, J = 6.5 Hz, 2H), 3.36–3.49 (m, 2H), 3.50–3.64
(m, 4H including 3.52, s, 2H), 4.40 (t, J = 5.5 Hz, 1H), 5.52 (brs,
1H), 7.18–7.35 (m, 5H); 13C NMR and DEPT (75 MHz, CDCl3)
d = 15.3 (CH3), 22.0 (CH2), 29.3 (CH2), 33.2 (CH2), 39.6 (CH2),
43.8 (CH2), 61.0 (CH2), 102.7 (CH), 127.3 (CH), 129.0 (CH), 129.4
(CH), 135.1 (C), 170.9 (C).
N - (5, 5 - Diethoxypentyl) - 2 - (3, 4 - dimethoxyphenyl) acetamide
(30). Isolated as an oil (88% yield). 1H NMR (300 MHz, CDCl3):
d = 1.16 (t, J = 7 Hz, 6H), 1.21–1.31 (m, 2H), 1.33–1.46 (m, 2H),
1.48–1.59 (m, 2H), 3.17 (q, J = 6.5 Hz, 2H), 3.36–3.49 (m, 4H
including 3.46, s, 2H), 3.50–3.64 (m, 2H), 3.86 (s, 6H), 4.40 (t,
J = 5.5 Hz, 1H), 5.45 (brs, 1H), 6.74–6.86 (m, 3H); 13C NMR and
DEPT (75 MHz, CDCl3) d = 15.3 (CH3), 22.1 (CH2), 29.5 (CH2),
39.5 (CH2), 43.7 (CH2), 55.9 (CH2), 61.1 (CH3), 61.3 (CH3), 102.5
(CH), 111.5 (CH), 112.4 (CH), 121.6 (C), 127.5 (C), 148.3 (C),
149.2 (C), 171.3 (C).
Acknowledgements
Natasha Spearing and Clare Holyoak (GSK, Harlow) are thanked
for providing the HPLC analyses, Dr. Lisa Harris (UCL) for the
mass spectra and GSK for initial funding.
1,2,3,4,7,11b-hexahydro-benzo[a]quinolizin-6-one
(31). Iso-
lated as a pale yellow solid (31% yield), mpt 47–49◦C (Et2O–
petrol) (lit. 49–52◦C21), HRMS theoretical mass: 201.1148,
measured mass: 201.1146. 1H NMR (500 MHz, CDCl3): d =
1.40–1.58 (m, 2H), 1.65–1.79 (m, 2H), 1.92–2.10 (m, 2H), 2.61
(td, J = 12.7, 2.5 Hz, 1H), 3.62 (d, J = 21.0 Hz, 1H), 3.67 (d,
J = 21.0 Hz, 1H), 4.42 (d, J = 11.8 Hz, 1H), 4.89 (ddt, J =
13.1, 4.2, 2.0 Hz, 1H), 7.08–7.35 (m, 4H); 13C NMR and DEPT
(125.8 MHz, CDCl3) d = 25.1 (CH2), 25.3 (CH2), 35.1 (CH2),
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