Intramolecular dipolar cycloaddition reactions to give substituted indoles - A formal synthesis of deethylibophyllidine

Article abstract of DOI:10.1002/ejoc.200700045

A four-step route to the tetracyclic ring system found in a number of indole alkaloids is described using stereoselective dipolar cycloaddition reactions of azomethine ylides. The ylides were derived from N-protected 2-butenylindole-3-carbaldehydes, which

Full text of DOI:10.1002/ejoc.200700045

FULL PAPER
DOI: 10.1002/ejoc.200700045
Intramolecular Dipolar Cycloaddition Reactions to Give Substituted Indoles –
A Formal Synthesis of Deethylibophyllidine
Iain Coldham,*[a] Benjamin C. Dobson,[a] Stephen R. Fletcher,[b] and Andrew I. Franklin[a]
Keywords: Cycloadditions / Azomethine ylides / Alkaloids / Pyrrolidines / Indoles
A four-step route to the tetracyclic ring system found in a
number of indole alkaloids is described using stereoselective
dipolar cycloaddition reactions of azomethine ylides. The
cloaddition with N-allylglycine, N-deallylation provided the
N-unsubstituted product and this constitutes a formal synthe-
sis of the alkaloid deethylibophyllidine. The cycloaddition
ylides were derived from N-protected 2-butenylindole-3-carb- chemistry was also shown to be amenable as a route to the
aldehydes, which were prepared in three steps from 2-
methylindole. Condensation of these aldehydes with a vari-
alkaloid ibophyllidine or epiibophyllidine, although the use
of 2-(allylamino)butyric acid to prepare the azomethine ylide
ety of alkylamino esters or amino acids or with N-methylhy- can favour competing iminium ion isomerisation and hydrol-
droxylamine gave the required azomethine ylides or nitrone
that undergo intramolecular cycloaddition onto the pendant,
unactivated alkene. The cycloaddition sets up two new rings
and up to three new stereocentres stereoselectively. After cy-
ysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
The iboga plant is a member of the family Apocynaceae
and contains a number of biologically active alkaloids.[1]
The roots of Tabernanthe iboga have been used in African
tribal initiation rites and confer hallucinogenic and stimu-
lant properties. This plant contains the alkaloid ibogaine
and a number of related alkaloids that have been used as
medicinal agents, with current interest in their “anti-ad-
dictive” properties.[2] Within this family are the ibophyllid-
ine group of alkaloids, including ibophyllidine, 20-epiibo-
phyllidine and deethylibophyllidine (Figure 1).[3] The first
synthesis of this type of alkaloid was reported by the group
of Kuehne using a Diels–Alder approach.[4] Subsequent re-
ports describe improved modifications of this chemistry.[5]
A similar approach was reported by Das and co-workers,
and by Kalaus and Szántay and co-workers.[6] A route using
the Fischer indole synthesis has been reported by Bonjoch
and co-workers,[7] who have also reported an alternative ap-
proach using a transannular cyclisation.[8] More recently
Padwa and co-workers have described an approach to this
type of alkaloid using a tandem Pummerer/Mannich cycli-
sation,[9] Banwell and Lupton have described a route to the
tricyclic core,[10] and Kalaus and Szántay and co-workers
have prepared 19-hydroxyibophyllidine.[11]
Figure 1. Ibophyllidine alkaloids.
One approach to polycyclic indole alkaloids involves the
Pummerer cyclisation of sulfoxides, with the indole ring act-
ing as the intramolecular nucleophile.[12] This was exploited
in Bonjoch’s synthesis, by addition of phenyl vinyl sulfoxide
to the secondary amine 2 (R = H) to give the sulfoxide 1
(R = H) (Scheme 1).[7] The sulfoxide 1 (R = H) was then
converted to deethylibophyllidine in 3 steps (Pummerer
cyclisation, desulfurisation and photochemical 1,3-acyl
shift). The amine 2 (R = H) was prepared in 6 steps from
O-methyltyramine.[7] We wondered if amines such as 2
could be accessed from azomethine ylides 3. These should
be readily available by addition of an amine to an indole-3-
carbaldehyde. The intramolecular cycloaddition of an azo-
methine ylide is an efficient method to prepare bicyclic
amines and can be successful even with an unactivated al-
kene as the dipolarophile.[13,14] A convenient approach to
such ylides involves the condensation of an aldehyde and
an amino acid, with loss of CO2 to give the desired ylide.[15]
[a] Department of Chemistry, University of Sheffield,
Brook Hill, Sheffield S3 7HF, UK
Fax: +44-114-222-9346
E-mail: i.coldham@shef.ac.uk
[b] Merck Sharp & Dohme,
Terlings Park, Harlow, UK
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Synthesis of Deethylibophyllidine
FULL PAPER
In fact, azomethine ylides have recently been generated
from indole-3-carbaldehydes by this methodology, although
these ylides subsequently undergo electrocyclic reaction
onto the pendent 2-phenyl substituent.[16] In the absence of
this phenyl group and in the presence of a dipolarophile,
we reasoned that the ylides should undergo cycloaddition.
We therefore investigated this approach and report here the
successful use of this chemistry for the formation of com-
pound 2 (R = H) and hence a formal synthesis of deethyl-
ibophyllidine.[17]
Scheme 2. Preparation of the aldehydes 7 and 8.
relative stereochemistry of this racemic major isomer was
confirmed by NOE spectroscopy. This showed the cis ring-
fused arrangement with the ethyl ester substituent cis to
these ring junction protons. This relative stereochemistry
conforms to cycloaddition through the expected S-shaped
azomethine ylide.[13] Attempted cycloaddition using the al-
dehyde 6 was unsuccessful.
Scheme 1. Retrosynthesis.
Results and Discussion
We needed a synthetic route to the aldehyde 7 in prepara-
tion for the key cycloaddition reactions. A route to the in-
dole 5, containing the required 2-butenyl chain, has been
described in the literature,[18] however this was lengthy and
low-yielding. We therefore explored the possibility of a
shorter route by carrying out a C-allylation of the dianion
generated from commercially available 2-methylindole (4).
The dianion of 4 can be prepared by double deprotonation
in the presence of a strong base and has been reported to
undergo methylation to give 2-ethylindole.[19] Using these
conditions, but with allyl bromide rather than iodomethane
as the electrophile, the product 5 was formed in reasonable
yield (Scheme 2). The deprotonation was best conducted
using either freshly sublimed tBuOK, or more easily, a solu-
tion of tBuOK in THF. The absence of either tBuOK or
nBuLi resulted in only recovered starting material 4. For-
mylation of the indole 5 was conducted under standard
conditions with POCl3 and DMF, and the product 6 was
converted into the aldehyde 7 by treatment with methyl
chloroformate and the base sodium hexamethyldisilazide
(NaHMDS) (or in similar yield under phase-transfer condi-
tions with 30% NaOH and 0.05 equiv. BnEt3NCl in
CH2Cl2 at 0 °C). Alternatively, the aldehyde 6 was protected
as the N-Boc derivative 8 by treatment with Boc2O.
Scheme 3. Cycloaddition with sarcosine ethyl ester.
Further examples of this type of cycloaddition of ester-
stabilised azomethine ylides are provided in Scheme 4, using
the aldehyde 8. The products 10 and 11 were formed in
good yield and as predominantly one stereoisomer (dr ≈ 7:1
based on 1H NMR spectroscopic analysis). As before, NOE
spectroscopy was used to verify the relative stereochemistry
and the coupling constant between the ring junction pro-
tons was the same as that for the cycloadduct 9 (J 6.0 Hz),
indicating a cis fused arrangement.
Initial attempts to form the azomethine ylide and hence
to investigate the potential for intramolecular cycloaddition
were performed using N-methylglycine ethyl ester (sarcosine
ethyl ester). Using an excess of this secondary amine as its
hydrochloride salt with the aldehyde 7 and diisopropylethyl-
Scheme 4. Further ester-stabilised ylide cycloadditions.
To show that this chemistry is amenable to other dipoles,
amine and heating under reflux in toluene gave the desired treatment of the aldehyde 7 with N-methylhydroxylamine
cycloadduct 9 (Scheme 3). The structure of the product was gave the intermediate nitrone and hence the cycloadduct 12
verified by 1H NMR spectroscopic analysis, and this (Scheme 5). This was formed as a single stereoisomer in
showed one major stereoisomer with a small amount of good yield. To confirm the cis stereochemistry at the ring
what was probably another, inseparable, diastereomer. The junction, the cycloadduct 12 was converted to compound
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I. Coldham, B. C. Dobson, S. R. Fletcher, A. I. Franklin
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13 by reduction of the N–O bond with zinc/AcOH and column chromatography on silica. The products correspond
treatment with p-bromobenzoyl chloride; subsequent X-ray to the stereoisomers 15, in which the ring junction protons
crystallographic structure analysis of the diacylated com- are cis to one another (confirmed by the coupling constants
pound 13 verified the expected structure and stereochemis- and by NOE spectroscopy on one of the isomers).
try (Figure 2).
Scheme 5. Nitrone cycloaddition.
Scheme 7. Cycloaddition with proline.
Application of this chemistry to the ibophyllidine alka-
loid ring system would ideally make use of an appropriate
N-substituted amino acid to condense with the aldehyde 7.
In particular, we envisaged that an N-arylthioethyl substitu-
ent would provide direct access to the required carbon skel-
eton for these alkaloids that would be suitable for subse-
quent S-oxidation (to give compound 1) and Pummerer
cyclisation. The amino acids 18, R = H or Et were prepared
from 2-oxazolidinone (Scheme 8). Initial N-alkylation using
NaH as the base proceeded efficiently with either tert-butyl
bromoacetate or tert-butyl bromobutyrate to give the oxaz-
olidinones 16a and 16b. These were opened with para-chlo-
rothiophenol and tBuOK as the base, following conditions
for related reactions reported by Ishibashi and co-
workers.[20] Finally, ester hydrolysis with HCl in dioxane
gave the desired amino acids 18 as their hydrochloride salts.
This represents an efficient entry to N-arylthioethyl amino
acids.
Figure 2. Structure and ORTEP plot of ester 13.
We then investigated the cycloaddition with non-stabi-
lised azomethine ylides generated from the aldehydes 7 and
8 and amino acids. In particular, heating these aldehydes
with N-methylglycine in toluene gave the desired cycload-
ducts 14a and 14b (Scheme 6). In both cases only the cis
ring-fused product was observed, and this was confirmed
for the product 14b by NOE spectroscopy.
Scheme 8. Preparation of N-arylthioethyl amino acids (Ar = p-
ClC6H4).
Scheme 6. Cycloaddition with sarcosine.
We were disappointed to find that all attempts to effect
Cycloaddition of the aldehyde 8 was also studied using cycloadditions of the aldehydes 7 or 8 with the amino acids
the amino acid proline (Scheme 7). A mixture of two stereo- 18a or 18b (or with the amino esters 17) failed. In all cases
isomeric products was obtained. These were separable by only recovered aldehyde was obtained together with, under
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Synthesis of Deethylibophyllidine
FULL PAPER
more forcing conditions, some of the aldehyde 6, in which product was isolated in low yield as a single stereoisomer
the N-protecting group had been removed. Treatment of the (stereochemistry undetermined). In this case the by-product
amino acid 18a with two equivalents of aqueous NaOH (in 21 was formed as the major product. We presume that the
H2O/THF, 1:1) gave the corresponding sodium carboxylate secondary amine 21 arises either from the intermediate im-
(after removal of the solvent by evaporation); however, inium ion 23 that undergoes isomerisation into conjugation
attempts to use this sodium salt in the cycloaddition also with the carboxylate, followed by hydrolysis, or by proton-
resulted in no reaction and only the starting aldehyde 7 was ation of the azomethine ylide 24 followed by hydrolysis of
recovered. It is possible that the sulfur atom participates to the iminium ion.
trap the intermediate iminium ion; hydrolysis of the re-
sulting S-arylthiazolidinium ion would re-form the alde-
hyde 7.
With the failure of the amino acids 18 to undergo cyclo-
addition with the aldehyde 7, we needed an alternative strat-
egy. We could have selected a different N-alkyl group, but
we chose first to explore the demethylation of the cycload-
duct 14a. One approach to demethylation of amines in-
volves the use of α-chloroethyl chloroformate followed by
heating the intermediate carbamate with methanol.[21] Tre-
ating the amine 14a under these conditions gave, not the
desired demethylated compound, but the carbazole 19 in
low yield (Scheme 9). This product likely arises from the
desired N-acylation, but instead of displacement of the
methyl group by the chloride ion, the molecule fragments
with breakage of the benzylic C–N bond. Subsequent elimi-
nation and aromatisation (plus hydrolysis of the chloroethyl
Scheme 10. Cycloaddition with N-allylglycine and 2-(allylamino)-
carbamate) provides 19.
butyric acid. a) CH2=CHCH2NHCH2CO2Na, PhMe, CSA, heat
gave 20, 42% and 21, Ͻ10%; b) CH2=CHCH2NHCH(Et)CO2Na,
PhMe, TsOH, heat gave 22, 19% and 21, 60%.
Although intramolecular dipolar cycloaddition reactions
are normally effective with unactivated alkenes as di-
polarophiles, we considered activating the alkene in the sub-
strate 7. This was achieved by conversion to the sulfone 25
using cross-metathesis (Scheme 11). Treatment of the sul-
fone 25 with N-allylglycine gave the desired cycloadduct 26.
The yield of this product was improved in comparison to
the cycloaddition in the absence of the sulfone substituent.
Scheme 9. Attempted demethylation of 14a.
None of the by-product akin to compound 21 was ob-
served. A single stereoisomer of the cycloadduct 26 was
produced, of undetermined stereochemistry, although
We therefore turned to the use of an N-alkyl group that
should be more readily removed from the cycloadduct. For
this we chose the N-allyl group and prepared N-allylglycine
by hydrolysis with NaOH of N-allylglycine ethyl ester.[22] In
the same way, we also prepared 2-(allylamino)butyric acid
by hydrolysis of ethyl 2-(allylamino)butyrate, itself prepared
by addition of allylamine to ethyl 2-bromobutyrate. Heating
the aldehyde 7 with N-allylglycine in toluene with cam-
phorsulfonic acid gave the desired cycloadduct 20 in moder-
ate yield (Scheme 10). Only one stereoisomer was formed,
which was assumed to have cis ring junction protons by
analogy with previous examples (coupling constant, J =
5.5 Hz in the 1H NMR spectrum). A by-product in this
reaction was also formed and was difficult to separate from
the cycloadduct 20. However, by careful column
chromatography some of the amine 21 was isolated. To ob-
tain a pure sample of the cycloadduct 20 it was found pref-
erable to treat the mixture of 20 and 21 with methyl chloro-
formate, as this reacts with the amine 21, and then to per-
form column chromatography. Heating the aldehyde 7 with
based on the examples described above this is likely to be
the isomer shown in Scheme 11. The chemistry therefore
verifies the expected improvement of the efficiency of the
cycloaddition in the presence of a sulfone substituent as an
2-(allylamino)butyric acid gave some cycloadduct 22. This Scheme 11. Cycloaddition with activated dipolarophile.
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I. Coldham, B. C. Dobson, S. R. Fletcher, A. I. Franklin
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(150 mL), followed by tBuOK (100 mL, 100 mmol, 1.0  in THF),
keeping the temperature below 20 °C. After 30 min the yellow solu-
tion was cooled to –78 °C. Allyl bromide (8.65 mL, 10 mmol) was
added dropwise over 45 min. After 2 h at –78 °C, MeOH (30 mL)
was added and the mixture was warmed to room temperature and
stirred for a further 1 h. MeOH (150 mL) and silica were added
and the solution was evaporated. Purification by column
chromatography, eluting with petrol/EtOAc (95:5), gave the indole
5 (5.84 g, 68%) as an oil; Rf = 0.61 [petrol/EtOAc (4:1)]. IR (neat):
activating group, and this strategy could find use in other
examples.[14d] With some of compound 20 to hand, how-
ever, we did not explore further the use of the activated
substrate 25.
All that was required to complete the formal synthesis
of racemic deethylibophyllidine was the N-deallylation of
compound 20 to give compound 2, R = H. In the presence
of Pd(dba)2, dppb and thiosalicylic acid,[23] the allyl group
was removed to give the desired product 2, R = H
ν
max
= 3405, 3075, 2920, 1640, 1615, 1585 cm–1. 1H NMR
˜
(Scheme 12). The spectroscopic data for this compound (250 MHz, CDCl3): δ = 7.71 (br. s, 1 H, NH), 7.56–7.49 (m, 1 H,
matched that reported in the literature.[7] The preparation
of this compound therefore completes a formal total syn-
thesis of the natural product deethylibophyllidine. Overall,
the tetracycle 2, R = H is formed from 2-methylindole in
ArH), 7.25–7.19 (m, 3 H, ArH), 6.24 (s, 1 H, CH), 5.89 (ddt, J =
17, 10, 6.5 Hz, 1 H, CH=), 5.16–4.97 (m, 2 H, =CH2), 2.77 (t, J =
7.5 Hz, 2 H, CH2) 2.49–2.32 (m, 2 H, CH2) ppm. 13C NMR
(63 MHz, CDCl3): δ = 139.3 (C), 137.8 (CH), 136.0 (C), 128.8 (C),
121.1 (CH), 119.9 (CH), 119.7 (CH), 115.7 (CH2), 110.5 (CH), 99.7
only 5 steps.
(CH), 33.3 (CH2), 27.7 (CH2) ppm. HRMS (ES) found: [M+],
171.1054, C12H13N requires [M+], 171.1048; data matches that in
the literature.[18]
2-(But-3-enyl)-1H-indole-3-carbaldehyde (6): POCl3 (10.7 mL,
116 mmol) was added to DMF (9.5 mL, 116 mmol) in CH2Cl2
(30 mL) at 0 °C over 30 min. The indole 5 (6.59 g, 39 mmol) in
CH2Cl2 (30 mL) was added, keeping the temperature below 10 °C.
The mixture was heated under reflux for 1 h, NaOH (20 mL, 2 )
was added and further heated under reflux for 1 h. The mixture
was cooled to room temperature, neutralised using NaOH (100 mL,
2 ) and extracted with CH2Cl2 (4ϫ75 mL). The organic phases
were dried (MgSO4), filtered and the solvents evaporated. Purifica-
tion by column chromatography, eluting with petrol/EtOAc (7:3),
followed by recrystallisation from petrol/EtOAc (1:1) gave the alde-
hyde 6 (6.35 g, 83%) as plates; m.p. 140–141 °C (dec.). Rf = 0.34
Scheme 12. Deallylation and completion of formal synthesis.
Conclusions
A short synthesis of a variety of tetracyclic amines con-
taining an indole unit has been accomplished. The chemis-
try uses an intramolecular [3+2] cycloaddition reaction of
an azomethine ylide as its key step. The cycloaddition reac-
tion sets up two new rings in a single step and is highly
stereoselective, with formation of only the cis-fused 6,5-ring
junction. The methodology has been applied to a formal
synthesis of the natural product deethylibophyllidine.
[petrol/EtOAc (1:1)]. IR (neat): νmax = 3080, 2795, 1615, 1580 cm–1.
˜
1H NMR (250 MHz, CDCl3): δ = 10.27 (s, 1 H, CHO), 9.72 (s, 1
H, NH), 8.41–8.32 (m, 1 H, ArH), 7.50–7.43 (m, 1 H, ArH), 7.40–
7.30 (m, 2 H, ArH), 5.96 (ddt, J = 17.0, 10.5, 6.5 Hz, 1 H,
CH=CH2), 5.25–5.12 (2 H, m CH=CH2), 3.30 (t, J = 7.5 Hz, 1 H,
CH2), 2.65 (dt, J = 7.5, 6.5 Hz, 2 H, CH2) ppm. 13C NMR
(63 MHz, CDCl3): δ = 184.7 (C=O), 136.4 (CH), 136.3 (C), 126.0
(C), 123.6 (CH), 122.9 (CH), 121.0 (CH), 121.1 (C), 116.9 (CH2),
114.3 (C), 111.2 (CH), 33.9 (CH2), 25.9 (CH2) ppm. HRMS (ES)
found: [MH+], 200.1073, C13H14NO requires [MH+], 200.1075;
LRMS (ES): m/z = 200 (100) [MH+], 172 (8) [MH+ – CO].
C13H13NO (199.10): calcd. C 78.36, H 6.58, N 7.03; found C 77.98,
H 6.51, N 6.93.
Experimental Section
General Comments: All experiments were carried out under argon
or nitrogen with freshly distilled solvents. Diethyl ether (Et2O) and
THF were distilled from sodium/benzophenone or were purified
using a Grubbs solvent purification system.[24] Petrol refers to light
petroleum (b.p. 40–60 °C). Column chromatography was performed
on silica gel (230–400 mesh). Infrared spectra were recorded with
a Nicolet Magna 550 FT-IR spectrometer or with a Perkin–Elmer
Spectrum RX1/FT IR system with a DuraSampl IR-II diamond
ATR. 1H and 13C NMR spectra were run with Bruker instruments
at various field strengths as indicated. Chemical shifts are reported
in parts per million (ppm) relative to solvent signals and coupling
constants, J, are given in Hz (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet). Mass spectra were run with a Micro-
mass GCT instrument or Micromass LCT. Low-resolution mass
spectra were recorded with a Thermoquest CE Trace GCMS2000
series instrument fitted with a Restek RTX-5MS (Cross bond 5%
diphenyl, 95% dimethyl polysiloxane 15-m column) with helium
as the carrier gas using either EI or CI mode. Microanalysis was
performed with a Carlo–Erba 1110 instrument.
Methyl
2-(But-3-enyl)-3-formyl-1H-indole-1-carboxylate
(7):
NaHMDS (18.6 mL, 18.6 mmol of a 1.0  solution in THF) was
added to the indole 6 (3.08 g, 15.5 mmol) in THF (200 mL) at
–78 °C. After 30 min MeOCOCl (1.56 mL, 20.1 mmol) was added
dropwise. After 90 min MeOH (25 mL) was added, and the mixture
was warmed to room temperature. The solvent was evaporated and
the residue was purified by column chromatography, eluting with
petrol/EtOAc (7:3), followed by recrystallisation from petrol/EtOAc
(1:1), to give the indole 7 (3.0 g, 78%) as needles; m.p. 81–82 °C.
R = 0.29 [petrol/EtOAc (4:1)]. IR (neat): ν
= 3065, 2955, 1740,
˜
f
max
1655, 1605, 1555 cm–1. H NMR (250 MHz, CDCl3): δ = 10.28 (s,
1 H, CHO), 8.35–8.27 (m, 1 H, ArH), 8.06–7.98 (m, 1 H, ArH),
7.38–7.30 (m, 2 H, ArH), 5.86 (ddt, J = 17.0, 10.5, 7.0 Hz, 1 H,
CH=CH2), 5.12–5.06 (m, 2 H, CH=CH2), 4.12 (s, 3 H, OCH3),
3.49 (t, J = 7.5 Hz, 2 H, CH2), 2.48 (q, J = 7.5 Hz, 2 H, CH2) ppm.
13C NMR (63 MHz, CDCl3): δ = 186.0 (C=O), 151.8 (C=O), 136.4
(CH), 135.4 (C), 126.0 (C), 125.4 (CH), 124.6 (CH), 121.2 (CH),
118.8 (C), 116.4 (C and CH2), 115.3 (CH), 54.3 (CH3), 34.3 (CH2),
25.8 (CH2) ppm. HRMS (ES) found: [MH+], 258.1130, C15H16NO3
1
2-(But-3-enyl)-1H-indole (5): nBuLi (60 mL, 150 mmol, 2.5  in
hexanes) was added to 2-methylindole (6.56 g, 50 mmol) and Et2O
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Synthesis of Deethylibophyllidine
FULL PAPER
requires [MH+], 258.1143; LRMS (ES): m/z = 258 (100) [MH+].
C15H15NO3 (257.11): calcd. C 70.02, H 5.88, N 5.44; found C
69.76, H 6.06, N 5.38.
1.86–1.78 (m, 1 H, CH), 1.66 (s, 9 H, tBu), 1.33 (t, J = 7.0 Hz, 3
H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.3 (C=O),
150.5 (C=O), 138.2 (C), 136.0 (C), 130.0 (C), 123.2 (CH), 122.4
(CH), 118.4 (CH), 115.5 (CH), 115.3 (C), 83.5 (C), 64.6 (CH), 60.1
(CH2), 57.1 (CH), 36.9 (CH3), 36.1 (CH), 33.9 (CH2), 28.2 (CH3),
27.8 (CH2), 24.8 (CH2), 14.4 (CH3) ppm. HRMS (ES) found:
[MH+], 399.2281, C23H31N2O4 requires [MH+], 399.2284. LRMS
(ES): m/z (%) = 399 (100) [MH+], 343 (40).
tert-Butyl 2-(But-3-enyl)-3-formyl-1H-indole-1-carboxylate (8):
Et3N (1.5 mL, 10.5 mmol), 4-(dimethylamino)pyridine (128 mg,
1.05 mmol) and Boc2O (2.29 g, 10.5 mmol) was added to a stirred
solution of the indole 6 (2.09 g, 10.5 mmol) in CH2Cl2 (50 mL) at
0 °C. After 16 h the solvent was evaporated and the residue was
purified by column chromatography, eluting with petrol/EtOAc
(4:1), to give the indole 8 (2.91 g, 90%) as needles; m.p. 67–68 °C.
2,6-Di-tert-Butyl
1-Methyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo-
[3,2-c]carbazole-2,6-dicarboxylate (11): N-Methylglycine tert-butyl
ester hydrochloride (874 mg, 4.8 mmol) and diisopropylethylamine
(1.66 mL, 9.5 mmol) was added to a stirred solution of the aldehyde
R = 0.90 [petrol/EtOAc (4:1)]. IR (neat): ν
= 3085, 2980, 1735,
˜
f
max
1660, 1550 cm–1. H NMR (250 MHz, CDCl3): δ = 10.28 (s, 1 H,
1
CHO), 8.34–8.28 (m, 1 H, ArH), 8.09–8.01 (m, 1 H, ArH), 7.37– 8 (569 mg, 1.2 mmol) in toluene (5 mL), and the mixture was
7.29 (m, 2 H, ArH), 5.86 (ddt, J = 17.0, 10.0, 6.5 Hz, 1 H,
CH=CH2), 5.12–5.00 (2 H, m CH=CH2), 3.50 (t, J = 7.5 Hz, 2 H,
CH2), 2.49 (q, J = 7.5 Hz, 2 H, CH2), 1.71 (s, 9 H, tBu) ppm. 13C
heated under reflux. After 96 h, the solvent was evaporated and the
residue was purified by column chromatography, eluting with pet-
rol/EtOAc (4:1), to give the amine 11 (299 mg, 59%) as an oil. Rf
NMR (63 MHz, CDCl3): δ = 185.9 (C=O), 151.7 (C=O), 149.5 (C), = 0.42 [petrol/EtOAc (4:1)]. IR (neat): νmax = 3065, 2930, 1730,
˜
136.4 (CH), 135.8 (C), 126.0 (C), 125.0 (CH), 124.4 (CH), 121.1
1640, 1605, 1575 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.21–8.15
(CH), 118.3 (C), 116.3 (CH2), 115.2 (CH), 85.7 (C), 34.5 (CH2), (m, 1 H, ArH), 7.69–7.64 (m, 1 H, ArH), 7.30–7.20 (m, 2 H, ArH),
28.1 (CH3), 25.7 (CH2) ppm. HRMS (ES) found: [MNa+], 4.42 (d, J = 6.0 Hz, 1 H, NCH), 3.78 (dd, J = 8.5, 4.5 Hz, 1 H,
322.1419, C18H21NO3Na requires [MNa+], 322.1420; LRMS (ES):
m/z (%) 322 (6) [MNa+], 244 (100). C18H21NO3 (299.15): calcd. C
72.22, H 7.07, N 4.68; found C 72.14, H 7.16, N 4.50.
CH), 3.23 (dt, J = 18.0, 5.0 Hz, 1 H, CH), 2.88–2.79 (m, 1 H, CH),
2.63 (s, 3 H, NCH3), 2.51–2.42 (m, 1 H, CH), 2.24 (ddd, J = 13.0,
8.0, 4.5 Hz, 1 H, CH), 2.08–1.95 (m, 2 H, 2 CH), 1.90–1.81 (m, 1
H, CH), 1.69 (s, 9 H, tBu), 1.57 (s, 9 H, tBu) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.0 (C=O), 150.6 (C=O), 138.3 (C),
136.0 (C), 130.1 (C), 123.3 (CH), 122.7 (CH), 118.5 (CH), 115.8
(C), 115.5 (CH), 83.5 (C), 80.8 (C), 65.4 (CH), 57.1 (CH), 36.9
(CH3), 36.2 (CH), 34.1 (CH2), 28.31 (CH3), 28.28 (CH3), 28.2
(CH2), 24.9 (CH2) ppm. HRMS (ES) found: [MH+], 427.2603,
C25H35N2O4 requires [MH+], 427.2597; LRMS (ES): m/z (%) = 427
(88) [MH+], 371 (100), 315 (49).
6-Methyl 1-Ethyl 1-Methyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo-
[3,2-c]carbazole-2,6-dicarboxylate (9): N-Methylglycine ethyl ester
hydrochloride (337 mg, 2.2 mmol) and diisopropylethylamine
(0.48 mL, 2.8 mmol) was added to a stirred solution of the aldehyde
7 (141 mg, 0.55 mmol) in toluene (5 mL), and the mixture was
heated under reflux. After 16 h, the solvent was evaporated and the
residue was purified by column chromatography, eluting with pet-
rol/EtOAc (7:3), to give the amine 9 (107 mg, 55%) as an oil. Rf =
0.34 [petrol/EtOAc (7:3)]. IR (neat): νmax = 2945, 1735, 1605 cm–1.
Methyl
1-Methyl-1,3,3a,4,5,10c-hexahydro-2-oxa-1,6-diazacyclo-
˜
1H NMR (250 MHz, CDCl3): δ = 8.05–7.97 (m, 1 H, ArH), 7.57– penta[c]fluorene-6-carboxylate (12): A solution of the aldehyde 7
7.50 (m, 1 H, ArH), 7.18–7.10 (m, 2 H, ArH), 4.32–4.27 (d, J =
6.0 Hz, 1 H, NCH), 4.14 (q, J = 7.0 Hz, 2 H, OCH2), 3.92 (s, 3 H,
OCH3), 3.75 (dd, J = 8.5, 4.5 Hz, 1 H, CHCO), 3.12 (dt, J = 18.5,
(132 mg, 0.52 mmol), N-methylhydroxylamine hydrochloride
(64 mg, 0.77 mmol) and diisopropylethylamine (0.13 mL,
0.77 mmol) in toluene (10 mL) was heated under reflux. After
5.0 Hz, 1 H, CH), 2.92–2.73 (m, 1 H, CH), 2.46 (s, 3 H, NCH3), 90 min, the solvent was evaporated and the residue was purified by
2.42–2.27 (m, 1 H, CH), 2.25–2.10 (m, 1 H, CH), 1.99–1.82 (m, 2
H, 2ϫCH), 1.81–1.66 (m, 1 H, CH), 1.24 (t, J = 7.0 Hz, 3 H, CH3)
ppm. 13C NMR (63 MHz, CDCl3): δ = 174.3 (C=O), 153.0 (C=O),
column chromatography, eluting with petrol/EtOAc (3:2), to give
the indole 12 (130 mg, 88%) as an oil. Rf = 0.50 [petrol/EtOAc
(3:2)]. IR (neat): ν
= 2945, 2865, 1735, 1610, 1580 cm–1. 1H
˜
max
138.4 (C), 135.9 (C), 130.2 (C), 123.6 (CH), 122.9 (CH), 118.6 NMR (250 MHz, CDCl3): δ = 8.04–8.00 (m, 1 H, ArH), 7.51–7.43
(CH), 116.0 (C), 115.5 (CH), 64.7 (CH3), 60.3 (CH2), 57.3 (CH3), (m, 1 H, ArH), 7.22–7.13 (m, 2 H, ArH), 4.22 (t, J = 8.0 Hz, 1 H,
53.4 (CH), 37.0 (CH), 36.2 (CH), 34.0 (CH2), 27.8 (CH2), 24.7 OCH), 3.94 (s, 3 H, OCH3), 3.86–3.81 (br, 1 H, NCH), 3.74–3.65
(CH2), 14.5 (CH3) ppm. HRMS (ES) found: [MH+], 357.1812,
C20H25N2O4 requires [MH+], 357.1814; LRMS (ES): m/z (%) = 357
(100) [MH+], 326 (9).
(m, 1 H, OCH), 3.16–3.06 (br. m, 1 H, CH), 2.99–2.86 (m, 2 H, 2
CH), 2.84 (s, 3 H, NCH3), 2.19–2.12 (m, 1 H, CH), 1.95–1.86 (m,
1 H, CH) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.4 (C=O),
138.0 (C), 136.0 (C), 129.1 (C), 123.8 (CH), 123.0 (CH), 117.8
(CH), 115.5 (CH), 113.8 (C), 70.0 (CH2), 63.5 (CH), 53.4 (CH3),
44.9 (CH3), 40.0 (CH), 24.8 (CH2), 22.8 (CH2) ppm. HRMS (ES)
found: [MH+], 287.1397, C16H19N2O3 requires [MH+], 287.1396;
LRMS (ES): m/z (%) = 287 (100) [MH+].
6-tert-Butyl 2-Ethyl 1-Methyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo-
[3,2-c]carbazole-2,6-dicarboxylate (10): N-Methylglycine ethyl ester
hydrochloride (630 mg, 4.1 mmol) and diisopropylethylamine
(0.88 mL, 5.1 mmol) was added to a stirred solution of the aldehyde
8 (305 mg, 1.0 mmol) in toluene (5 mL), and the mixture was
heated under reflux. After 18 h, the solvent was evaporated and the
residue was purified by column chromatography, eluting with pet-
Methyl 4-[(4-Bromobenzoyl)methylamino]-3-(4-bromobenzoyloxy-
methyl)-1,2,3,4-tetrahydrocarbazole-9-carboxylate (13): A solution
rol/EtOAc (9:1), to give the amine 10 (324 mg, 80%) as an oil. Rf of the cycloadduct 12 (126 mg, 0.44 mmol), acetic acid (1.7 mL),
= 0.33 [petrol/EtOAc (4:1)]. IR (neat): ν = 2980, 1725, 1665 water (3.3 mL) and zinc (121 mg, 1.8 mmol) was heated at 70 °C.
cm–1. H NMR (500 MHz, CDCl3): δ = 8.15–8.11 (m, 1 H, ArH), After 2 h, the mixture was filtered through Celite, the solvent was
˜
max
1
7.62–7.60 (m, 1 H, ArH), 7.26–7.18 (m, 2 H, ArH), 4.39 (d, J =
6.0 Hz, 1 H, NCH), 4.23 (q, J = 7.0 Hz, 2 H, OCH2), 3.82 (dd, J
= 8.5, 4.5 Hz, 1 H, CH), 3.20 (dt, J = 18.0, 5.0 Hz, 1 H, CH), 2.95
evaporated and the residue was extracted from 10% aqueous
NH4OH with CH2Cl2 (4ϫ20 mL), dried (MgSO4) and the solvents
evaporated. To the residue was added CH2Cl2 (10 mL), 4-dimethyl-
(ddd, J = 18.0, 9.5, 6.0 Hz, 1 H, CH), 2.55 (s, 3 H, NCH3), 2.49– aminopyridine (54 mg, 0.44 mmol), Et3N (0.37 mL, 2.6 mmol) and
2.41 (m, 1 H, CH), 2.24 (ddd, J = 13.0, 8.0, 5.0 Hz, 1 H, CH), 2.02
(ddd, J = 13.0, 9.0, 3.5 Hz, 1 H, CH), 1.99–1.92 (m, 1 H, CH),
4-bromobenzoyl chloride (480 mg, 2.2 mmol) at room temperature.
After 16 h, aqueous NaHCO3 (25 mL) was added and the mixture
Eur. J. Org. Chem. 2007, 2676–2686
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2681

I. Coldham, B. C. Dobson, S. R. Fletcher, A. I. Franklin
FULL PAPER
was extracted with CH2Cl2 (3ϫ20 mL), dried (MgSO4) and the
solvents evaporated. The solid product was recrystallised from pet-
rol/EtOAc to give the ester 13 (183 mg, 63%) as cubes; m.p. 190–
3.21 (d, J = 5.5 Hz, 1 H, CH), 3.18–3.10 (m, 1 H, CH), 3.10–3.05
(m, 1 H, CH), 2.79 (ddd, J = 17.5, 11, 6 Hz, 1 H, CH), 2.42 (s, 3
H, NCH3), 2.32–2.25 (m, 1 H, CH), 2.17–2.09 (m, 1 H, CH), 2.05–
191 °C. R = 0.42 [petrol/EtOAc (7:3)]. IR (neat): ν
= 3340, 1.93 (m, 2 H, 2ϫCH), 1.78–1.70 (m, 1 H, CH), 1.56 (s, 9 H, tBu),
˜
f
max
3060, 2970, 2920, 2855, 1735, 1715, 1630, 1590 cm–1. 1H
1.53–1.47 (m, 1 H, CH) ppm. 13C NMR (126 MHz, CDCl3): δ =
NMR(250 MHz, CDCl3) 8.06 (d, 1 H, J 8.5, ArH), 7.94–7.85 (m,
150.5 (C=O), 138.1 (C), 136.1 (C), 129.9 (C), 123.5 (CH), 122.5
3 H, ArH), 7.64–7.42 (m, 4 H, ArH), 7.32–7.17 (m, 4 H, ArH), (CH), 118.3 (CH), 115.5 (C), 115.4 (CH), 83.4 (C), 61.3 (CH), 55.8
6.47 (d, 1 H, J 5.5, CH), 4.59–4.44 (m, 2 H, CH2), 4.00 (s, 3 H, (CH2), 42.3 (CH3), 36.2 (CH), 29.0 (CH2), 28.2 (CH3), 28.1 (CH2),
OCH3), 3.40 (dd, 1 H, J 18.0, 5.0, CH), 3.00–2.91 (m, 1 H, CH),
2.62 (s, 3 H, NCH3), 2.60–2.55 (m, 1 H, CH), 2.12–2.04 (m, 1 H,
25.5 (CH2) ppm. HRMS (ES) found: [MH+], 327.2073,
C20H27N2O2 requires [MH+], 327.2060. LRMS (ES): m/z (%) = 327
CH), 1.88–1.77 (m, 1 H, CH). 13C NMR (100 MHz, CDCl3) 171.6 (100) [MH+], 271 (8).
(C=O), 166.0 (C=O), 152.3 (C=O), 138.9 (C), 135.9 (C), 135.6 (C),
Pentacycles 15a and 15b: Proline (348 mg, 3.0 mmol) was added to
131.7 (CH), 131.3 (CH), 130.2 (C), 128.9 (C), 128.2 (CH), 128.2
(C), 124.5 (CH), 123.7 (C), 123.6 (CH), 118.3 (CH), 115.6 (CH),
114.5 (C), 65.6 (CH2), 53.6 (CH3), 45.2 (CH), 37.8 (CH3), 35.5
(CH), 24.6 (CH2), 23.1 (CH2). HRMS (ES) found: [MNa+],
675.0081, C30H26Br2N2O5Na requires [MNa+], 675.0106. LRMS
(ES): m/z (%) = 677 (14) [MNa+], 655 (7) [MH], 442 (97), 440 (100).
C30H26Br2N2O5 (652.02): calcd. C 55.07, H 4.00, Br 24.42, N 4.28;
found C 55.29, H 3.88, Br 24.31, N 4.09.
the aldehyde 8 (226 mg, 0.76 mmol) in dioxane (20 mL) and the
mixture was heated at 110 °C. After 20 h, the solvent was evapo-
rated and the residue was purified by column chromatography, elut-
ing with CH2Cl2/MeOH/NH3 (95:5:0.1), to give the amines 15a and
15b (181 mg, 68%, 1:1) as oils; data for less polar product: Rf =
0.54 [CH Cl /MeOH/NH (9:1:0.1)]. IR (neat): ν = 3050, 2925,
˜
max
2
2
3
2865, 2800, 1725, 1605 cm–1. 1H NMR (500 MHz, CDCl3): δ =
8.12–8.07 (m, 1 H, ArH), 7.60–7.56 (m, 1 H, ArH), 7.23–7.16 (m,
2 H, ArH), 3.87 (d, J = 5.5 Hz, 1 H, CH), 3.86–3.80 (m, 1 H, CH),
3.40 (ddd, J = 9.5, 6.5, 3 Hz, 1 H, CH), 3.22 (ddd, J = 18, 6, 4 Hz,
1 H, CH), 3.04 (dt, J = 9.5, 6 Hz, 1 H, CH), 2.87 (ddd, J = 17, 10,
6 Hz, 1 H, CH), 2.57–2.50 (m, 1 H, CH), 2.11–1.99 (m, 3 H, 3
CH), 1.99–1.85 (m, 3 H, 3 CH), 1.78–1.69 (m, 1 H, CH), 1.64 (s,
9 H, tBu), 1.52–1.43 (m, 1 H, CH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 150.6 (C=O), 136.3 (C), 136.1 (C), 129.5 (C), 123.2
(CH), 122.3 (CH), 118.4 (CH), 118.1 (C), 115.4 (CH), 83.3 (C),
64.4 (CH), 62.5 (CH), 56.8 (CH2), 41.3 (CH), 40.2 (CH2), 31.0
(CH2), 28.2 (CH3), 28.1 (CH2), 25.6 (CH2), 24.5 (CH2) ppm.
HRMS (ES) found: [M+], 352.2161, C22H28N2O2 requires [M+],
352.2151; LRMS (ES): m/z (%) = 352 (13) [M+], 243 (100). NOESY
on the less polar product was possible on selected isolated peaks
and showed enhancement between the vicinal ring junction protons
(α and β to the indole 3-position) (3.7 and 3.9%) and enhancement
between the proton β to the indole 3-position and a vicinal proton
(presumably cis) in the pyrrolidine (γ to the indole 3-position) (3.5
and 5.1%); in addition there was no enhancement between this
proton at the γ position and the vicinal proton at the ring junction
of the pyrrolidine (δ to the indole 3-position) that was added as
proline – although not conclusive, this data suggests that the less
polar product has the structure 15a; data for more polar product:
X-ray Crystallography of Ester 13: Triclinic crystal system, space
¯
group P1. Unit cell dimensions a = 9.3822(4) Å, α = 85.372(2)°, b
= 11.6384(5) Å, β = 76.381(2)°, c = 13.3734(6) Å, γ = 83.273(2)°,
V = 1407.33(11) Å3, Z = 2, dcalcd. = 1.544 mg/m3. Absorption coef-
ficient
=
2.922 mm–1. F(000)
=
660. Crystal size
0.35ϫ0.28ϫ0.19 mm3. Reflections collected 34124, independent
reflections 6043 [Rint = 0.0347]. Full-matrix least-squares on F2 re-
finement method. Goodness-of-fit on F2 = 1.074.
CCDC-629950 contains supplementary crystallographic data for
13. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
6-Methyl 1-Methyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo[3,2-c]car-
bazole-6-carboxylate (14a): N-methylglycine (178 mg, 1.9 mmol)
was added to a stirred solution of the aldehyde 7 (128 mg,
0.5 mmol) in toluene (10 mL) and the mixture was heated under
reflux. After 21 h, the solvent was evaporated and the residue was
purified by column chromatography, eluting with CH2Cl2/MeOH
(95:5), to give the amine 14a (141 mg, 69%) as an oil. Rf = 0.22
[CH Cl /MeOH (9:1)]. IR (neat): νmax = 2950, 1725, 1610 cm–1. 1H
˜
2
2
NMR (500 MHz, CDCl3): δ = 8.2l–8.06 (m, 1 H, ArH), 7.54–7.51
(m, 1 H, ArH), 7.20–7.12 (m, 2 H, ArH), 3.93 (s, 3 H, OCH3), 3.49
(d, J = 4.5 Hz, 1 H NCH), 3.29–3.24 (m, 1 H, CH), 3.23–3.19 (m,
1 H, CH), 2.87 (ddd, J = 17.5, 11.5, 6.0 Hz, 1 H, CH), 2.58 (s, 3
H, NCH3), 2.51–2.45 (m, 1 H, CH), 2.34–2.22 (m, 1 H, CH), 2.20–
2.12 (m, 1 H, CH), 2.13–2.01 (m, 1 H, CH), 1.92–1.87 (m, 1 H,
CH), 1.59–1.51 (m, 1 H, CH) ppm. 13C NMR (125 MHz, CDCl3):
δ = 152.4 (C=O), 138.5 (C), 136.0 (C), 130.0 (C), 123.5 (CH), 122.8
(CH), 118.5 (CH), 115.3 (CH), 115.1 (C), 61.4 (CH), 55.7 (CH2),
53.4 (CH3) 42.1 (CH3), 36.7 (CH), 29.0 (CH2), 27.7 (CH2), 25.0
(CH2) ppm. HRMS (ES) found: [MH+], 285.1596, C17H21N2O2 re-
quires [MH+], 285.1603; LRMS (ES): m/z (%) = 285 (100) [MH+].
R = 0.44 [CH Cl /MeOH/NH (9:1:0.1)]. IR (neat): ν = 3060,
˜
max
f
2
2
3
2935, 2865, 1730, 1605 cm–1. 1H NMR (500 MHz, CDCl3): δ =
8.11–8.07 (m, 1 H, ArH), 7.84–7.98 (m, 1 H, ArH), 7.27–7.20 (m,
2 H, ArH), 4.46 (d, J = 5 Hz, 1 H, CH), 3.92–3.83 (m, 1 H, CH),
3.25 (ddd, J = 18, 5, 3 Hz, 1 H, CH), 2.87–2.79 (m, 1 H, CH),
2.78–2.72 (m, 1 H, CH), 2.72–2.65 (m, 1 H, CH), 2.49–2.42 (m, 1
H, CH), 2.42–2.34 (m, 1 H, CH), 2.22–2.14 (m, 1 H, CH), 2.05–
1.97 (m, 1 H, CH), 1.87–1.78 (m, 2 H, 2ϫCH), 1.67 (s, 9 H, tBu),
1.65–1.56 (m, 1 H, CH), 1.47–1.39 (m, 2 H, 2 CH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 150.5 (C=O), 138.5 (C), 135.9 (C), 129.2
(C), 123.7 (CH), 122.9 (CH), 119.2 (CH), 117.1 (C), 115.2 (CH),
83.7 (C), 65.4 (CH), 57.9 (CH), 49.6 (CH2), 39.6 (CH), 37.4 (CH2),
32.7 (CH2), 28.2 (CH2), 28.1 (CH3), 26.1 (CH2), 25.3 (CH2) ppm.
HRMS (ES) found: [M+], 352.2150, C22H28N2O2 requires [M+],
352.2151; LRMS (ES): m/z (%) = 352 (9) [M+], 243 (100).
6-tert-Butyl 1-Methyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo[3,2-c]-
carbazole-6-carboxylate (14b): N-Methylglycine (554 mg, 6.2 mmol)
was added to a stirred solution of the aldehyde 8 (400 mg,
1.55 mmol) in toluene (10 mL) and the mixture was heated under
reflux. After 72 h, the solvent was evaporated and the residue was
purified by column chromatography, eluting with CH2Cl2/MeOH/
tert-Butyl (2-Oxo-1,3-oxazolidin-3-yl)acetate (16a): NaH (2.4 g,
60 mmol, 60% dispersion in mineral oil) was added to a stirred
NH3 (99:1:0.1), to give the amine 14b (194 mg, 44%) as an oil. Rf solution of 2-oxazolidinone (5.65 g, 58.6 mmol) in THF (80 mL) at
= 0.43 [CH Cl /MeOH (95:5)]. IR (neat): ν = 2935, 2765, 1725 0 °C. After 30 min tert-butyl bromoacetate (13.0 mL, 87.9 mmol)
˜
max
2
2
cm–1. H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 7.5 Hz, 1 H,
was added dropwise. The mixture was warmed to room tempera-
1
ArH), 7.47 (d, J = 8.5 Hz, 1 H, ArH), 7.16–7.07 (m, 2 H, ArH), ture over 16 h. Water (60 mL) was added followed by EtOAc
2682
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2676–2686

Synthesis of Deethylibophyllidine
FULL PAPER
(60 mL), the phases were separated and the aqueous phase was
extracted with EtOAc (4ϫ50 mL). The combined organic phases
were washed with brine (200 mL), dried (MgSO4) and evaporated
to give the oxazolidinone 16a (11.8 g, 72%) as needles; m.p. 82–
2-propanol, the HCl salt of the amino ester 17b (6.05 g, 80%) as
needles; m.p. 132–133 °C. Rf = 0.75 [petrol/EtOAc (1:1)]. IR (neat):
ν
= 3390, 2970, 2790, 1740, 1560 cm–1. 1H NMR (250 MHz,
˜
max
CD3OD): δ = 7.47–7.38 (m, 2 H, ArH), 7.37–7.29 (m, 2 H, ArH),
3.95–3.88 (dd, J = 6.5, 5.0 Hz, 1 H, CH), 3.31–3.04 (m, 4 H,
83 °C. R = 0.23 [petrol/EtOAc (1:1)]. IR (neat): νmax = 2970, 1760,
˜
f
1740 cm–1. 1H NMR (360 MHz, CDCl3): δ = 4.39–4.35 (t, J = CH2CH2), 2.10–1.85 (m, 2 H, CH2), 1.46 (s, 9 H, tBu), 1.04–0.95
8.0 Hz, 2 H, CH2), 3.92 (s, 2 H, CH2), 3.73–3.68 (t, J = 8.0 Hz, 2 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR (63 MHz, CD3OD): δ =
H, CH2), 1.48 (s, 9 H, tBu) ppm. 13C NMR (90 MHz, CDCl3): δ
169.0 (C=O), 134.4, (C), 133.8 (C), 133.0 (CH), 130.6 (CH), 85.9
(C), 62.7 (CH), 46.9 (CH2), 30.5 (CH2), 28.1 (CH3), 24.0 (CH2),
= 167.8 (C=O), 158.4 (C=O), 82.9 (C), 62.5 (CH2), 46.5, (CH2)
45.3 (CH2), 28.4 (CH3) ppm. HRMS (EI) found: [M+], 201.1006, 9.3 (CH3) ppm. HRMS (ES) found: [M+
– Cl], 330.1292,
C9H15NO4 requires [M+], 201.1001; LRMS (EI): m/z (%) = 201 (2)
[M+], 101 (100). C9H15NO4 (201.10): calcd. C 53.72, H 7.51, N
6.96; found C 53.79, H 7.25, N 6.97.
C16H25ClNO2S requires [M+ – Cl], 330.1295; LRMS (ES): m/z (%)
= 330 (37) [MH+], 274 (100). C16H25Cl2NO2S (365.10): calcd. C
52.46, H 6.88, N 3.82, Cl 19.35, S 8.75; found C 52.41, H 6.63, N
4.11, Cl 19.33, S 8.92.
tert-Butyl (2-Oxo-1,3-oxazolidin-3-yl)butyrate (16b): NaH (3.2 g,
135 mmol, 60% dispersion in mineral oil) was added to 2-oxazolid-
inone (10.65 g, 122 mmol) in THF (125 mL) at 0 °C. After 30 min
tert-butyl 2-bromobutyrate (25.1 mL, 159 mmol) was added drop-
wise, then the mixture was heated under reflux for 16 h. Water
(60 mL) was added followed by EtOAc (60 mL), the phases were
separated and the aqueous phase was extracted with EtOAc
(4ϫ50 mL). The combined organic phases were washed with brine
(200 mL), dried (MgSO4) and the solvents evaporated. Purification
by column chromatography, eluting with petrol/EtOAc (7:3), gave
the oxazolidinone 16b (19.8 g, 71%) as an oil. Rf = 0.53 [petrol/
{2-[4-(Chlorophenyl)thio]ethyl}aminoacetic Acid, HCl Salt (18a):
Anhydrous HCl (100 mL, 4  solution in dioxane) was added to
the ester 17a (6.29 g, 21 mmol) and the mixture was warmed to
50 °C. After 1 h the solvent was evaporated to give, after recrystalli-
sation from 2-propanol, the amino acid 18a (3.81 g, 65%) as need-
les; m.p. 197–198 °C. Rf = 0.24 [CH2Cl2/MeOH (4:1)]. IR (neat):
ν
max = 2890, 2790, 1745, 1640 cm–1. 1H NMR (250 MHz, CD3OD):
˜
δ = 7.25–7.19 (m, 2 H, ArH), 7.17–7.09 (m, 2 H, ArH), 3.72 (s, 2
H, CH2), 3.10–3.00 (m, 4 H, CH2CH2) ppm. 13C NMR (90 MHz,
CD3OD): δ = 169.1 (C=O), 134.9 (C), 134.1 (C), 133.5 (CH), 131.0
EtOAc (1:1)]. IR (neat): ν
= 1740, 1735 cm–1. 1H NMR (CH), 48.7 (CH2), 48.0 (CH2), 31.0 (CH2) ppm. HRMS (ES) found:
˜
max
(250 MHz, CDCl3): δ = 4.34–4.23 (m, 2 H, CH2), 4.17–4.13 (dd, J [M+ – Cl], 246.0356, C10H13ClNO2S requires [M+ – Cl], 246.0351;
= 11.0, 5.0 Hz, 1 H, CH), 3.74–3.69 (m, 1 H, CH), 3.46–3.40 (m, LRMS (ES): m/z (%) = 246 (100) [MH+]. C10H13Cl2NO2S (281.00):
1 H, CH), 1.95–1.86 (m, 1 H, CH), 1.61–1.52 (m, 1 H, CH), 1.36 calcd. C 42.56, H 4.64, N 4.96, Cl 25.13, S 11.36; found C 42.29,
(s, 9 H, tBu), 0.91–0.86 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR
(126 MHz, CDCl3): δ = 169.9 (C=O), 158.7 (C=O), 81.8 (C), 62.2
(CH2), 57.6 (CH), 41.0 (CH2), 27.9 (CH3), 22.3 (CH2), 10.7 (CH3)
ppm. HRMS (EI) found: [M+], 229.1314, C11H19NO4 requires
[M+], 229.1323; LRMS (EI): m/z (%) = 229 (2) [M+], 128 (100).
H 4.42, N 5.04, Cl 24.94, S 11.35.
{2-[4-(Chlorophenyl)thio]ethyl}aminobutyric Acid, HCl Salt (18b):
Anhydrous HCl (80 mL, 4  solution in dioxane) was added to the
ester 17b (3.05 g, 9 mmol) and the mixture was warmed to 50 °C.
After 1 h the solvent was evaporated to give, after recrystallisation
tert-Butyl {2-[4-(Chlorophenyl)thio]ethyl}aminoacetate, HCl Salt from 2-propanol, the amino acid 18b (2.1 g, 81%) as needles; m.p.
(17a): Potassium tert-butoxide (1.06 g, 9.4 mmol) was added to a
stirred solution of 4-chlorothiophenol (1.77 g, 12.2 mmol) in tert-
butyl alcohol (35 mL). After 10 min the oxazolidinone 16a (1.73 g,
8.6 mmol) was added and the mixture was heated under reflux.
After 22 h the solvent was evaporated and the residue was dissolved
in Et2O (30 mL) and HCl (25 mL, 0.5 ) was added. The mixture
was filtered and dried (MgSO4) to give, after recrystallisation from
2-propanol, the HCl salt of the amino ester 17a (2.89 g, 92%) as
needles; m.p. 128–129 °C. Rf = 0.43 [petrol/EtOAc (1:1)]. IR (neat):
191–192 °C. R = 0.42 [CH Cl /MeOH (4:1)]. IR (neat): ν
=
˜
f
2
2
max
2975, 2800, 1730, 1550 cm–1. 1H NMR (400 MHz, CD3OD): δ =
7.37–7.34 (m, 2 H, ArH), 7.28–7.25 (m, 2 H, ArH), 3.91 (dd, J =
11.5, 5.0 Hz, 1 H, CH), 3.25–3.10 (m, 4 H, CH2CH2), 1.99–1.85
(m, 2 H, CH2), 0.94 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR
(90 MHz, CD3OD): δ = 171.8 (C=O), 134.5 (C), 134.3 (C), 133.3
(CH), 131.0 (CH), 62.7 (CH), 47.5 (CH2), 30.9 (CH2), 24.3 (CH2),
9.7 (CH3) ppm. HRMS (ES) found: [M+
C12H17ClNO2S requires [M+ – Cl], 274.0675. LRMS (ES): m/z (%)
– Cl], 274.0669,
ν
˜
max = 3380, 2985, 1735, 1655 cm–1. 1H NMR (400 MHz, CDCl3): = 274 (100) [MH+]. C12H17Cl2NO2S (309.04): calcd. C 46.46, H
δ = 7.42–7.40 (d, J = 8.5 Hz, 2 H, ArH), 7.27 (d, J = 8.5 Hz, 2 H, 5.52, N 4.51, Cl 22.85, S 10.34; found C 46.34, H 5.52, N 4.67, Cl
ArH), 3.79 (s, 2 H, CH2), 3.54–3.51 (t, J = 8.0 Hz, 2 H, CH2),
3.28–3.24 (t, J = 8.0 Hz, 2 H, CH2), 1.46 (s, 9 H, tBu) ppm. 13C
NMR (90 MHz, CDCl3): δ = 165.1 (C=O), 133.4, (C), 132.4 (C),
131.7 (CH), 129.8 (CH), 85.1 (C), 48.3 (CH2), 47.2 (CH2), 29.5
(CH2), 28.3 (CH3) ppm. HRMS (ES) found: [M+ – Cl], 302.0970,
C14H21ClNO2S requires [M+ – Cl], 302.0982. LRMS (ES): m/z (%)
= 302 (88) [MH+], 246 (100). C14H21Cl2NO2S (337.07): calcd. C
49.71, H 6.26, N 4.14, Cl 20.96, S 9.48; found C 49.45, H 6.47, N
3.84, Cl 20.78, S 9.52.
22.62, S 10.32.
Methyl 3-(2-Methylaminoethyl)carbazole-9-carboxylate (19): 1-
Chloroethyl chloroformate (0.07 mL, 0.6 mmol) was added to the
amine 13 (164 mg, 0.6 mmol) in PhMe (15 mL) and the mixture
was heated under reflux. After 16 h the solvent was evaporated and
the residue was purified by column chromatography, eluting with
petrol/EtOAc (4:1), to give the intermediate carbamate, which was
dissolved in MeOH (40 mL) and heated at 40 °C. After 2 d, the
solvent was evaporated and the residue was purified by column
chromatography, eluting with CH2Cl2/MeOH (4:1), to give the
amine 19 (45 mg, 27%), recrystallised from petrol/CH2Cl2 as plates;
m.p. 191–192 °C (dec.). Rf = 0.29 [CH2Cl2/MeOH (9:1)]. IR (neat):
tert-Butyl {2-[4-(Chlorophenyl)thio]ethyl}aminobutyrate, HCl Salt
(17b): Potassium tert-butoxide (2.88 g, 25.6 mmol) was added to a
stirred solution of 4-chlorothiophenol (3.71 g, 25.6 mmol) in tert-
butyl alcohol (110 mL). After 10 min the oxazolidinone 16b (5.35 g,
23.3 mmol) was added and the mixture was heated under reflux.
After 26 h the solvent was evaporated and the residue was dissolved
in Et2O (100 mL) and HCl (30 mL, 0.5 ) was added. The mixture
was filtered and dried (MgSO4) to give, after recrystallisation from
ν
= 3050, 2950, 2770, 1735, 1655, 1605, 1580 cm–1. 1H NMR
˜
max
(250 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 1 H, ArH), 8.04 (d, J
= 8.0 Hz, 1 H, ArH), 7.80–7.69 (m, 2 H, ArH), 7.39–7.30 (m, 1 H,
ArH), 7.25–7.16 (m, 2 H, ArH), 4.00 (s, 3 H, OCH3), 3.35–3.13
(m, 4 H, CH2CH2), 2.67 (s, 3 H, NCH3) ppm. 13C NMR (63 MHz,
Eur. J. Org. Chem. 2007, 2676–2686
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2683

I. Coldham, B. C. Dobson, S. R. Fletcher, A. I. Franklin
FULL PAPER
CDCl3): δ = 152.7 (C=O), 138.4 (C), 137.2 (C), 131.2 (C), 127.5
(m, 1 H, CH), 3.54 (d, J = 5.5 Hz, 1 H, CH), 3.22 (ddd, J = 18.5,
(CH), 127.4 (CH), 126.4 (C), 125.4 (C), 123.4 (CH), 119.7 (2 CH), 5.5, 4.0 Hz, 1 H, CH), 3.18–3.12 (m, 1 H, CH), 3.01 (dd, J = 12.5,
116.5 (CH), 116.1 (CH), 53.5 (CH3), 51.0 (CH2), 33.2 (CH3), 32.3
(CH2) ppm. HRMS (ES) found: [MH+], 283.1457, C17H19N2O2 re-
quires [MH+], 283.1447. LRMS (ES): m/z (%) = 283 (100) [MH+],
252 (49).
8.0 Hz, 1 H, CH), 2.94–2.85 (m, 1 H, CH), 2.36–2.29 (m, 1 H, CH),
2.29–2.22 (m, 1 H, CH), 2.16–2.04 (m, 2 H, 2 CH), 1.87–1.80 (m,
1 H, CH), 1.63–1.56 (m, 1 H, CH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 152.6 (C=O), 138.2 (C), 136.7 (CH), 136.0 (C), 130.2
(C), 123.4 (CH), 122.8 (CH), 118.6 (CH), 116.5 (CH2), 116.4 (C),
115.4 (CH), 60.1 (CH), 58.9 (CH2), 53.3 (CH3), 52.3 (CH2), 36.3
(CH), 28.6 (CH2), 27.6 (CH2), 24.9 (CH2) ppm. HRMS (ES) found:
[MH+], 311.1755, C19H23N2O2 requires [MH+], 311.1760. LRMS
(ES): m/z (%) = 311 (100) [MH+].
Sodium Allylaminoacetate: To a stirred solution of ethyl allylami-
noacetate[25] (1.48 g, 10.3 mmol) in THF (10 mL) and H2O (10 mL)
was added NaOH (0.41 g, 10.3 mmol). After 16 h the mixture was
washed with petrol, then evaporated to give the title compound
(1.27 g, 90%) as a solid; m.p. 237–238 °C (dec.). IR (neat): ν
=
˜
max
3310, 3075, 3005, 2815, 1635, 1580 cm–1. 1H NMR (250 MHz,
D2O): δ = 5.67 (ddt, J = 16.5, 10.5, 6.0 Hz, 1 H, CH=), 5.05–4.88
(m, 2 H, CH2=), 3.01–2.90 (m, 4 H, 2 CH2) ppm. 13C NMR
(63 MHz, D2O): δ = 179.3 (C=O), 135.1 (CH), 117.0 (CH2), 51.1
(CH2), 50.4 (CH2) ppm. HRMS (ES) found: [MNa+], 160.0358,
C5H8NO2Na requires [MNa+], 160.0350.
Methyl 3-(Allylaminomethyl)-2-but-3-enylindole-1-carboxylate (21):
R = 0.40 [CH Cl /MeOH (95:5)]. IR (neat): ν = 3340, 3070,
˜
max
f
2
2
2930, 2855, 1735, 1640, 1605, 1575 cm–1. 1H NMR (250 MHz,
CDCl3): δ = 8.02–7.93 (m, 1 H, ArH), 7.55–7.46 (m, 1 H, ArH),
7.22–7.10 (m, 2 H, ArH), 5.95–5.69 (m, 2 H, 2ϫHC=), 5.19–4.85
(m, 4 H, 2ϫ =CH2), 3.95 (s, 3 H, OCH3), 3.76 (s, 2 H, CH2), 3.25–
3.19 (m, 2 H, CH2), 3.12–3.03 (m, 2 H, CH2), 2.30 (q, J = 7.5 Hz,
2 H, CH2) ppm. 13C NMR (63 MHz, CDCl3): δ = 152.4 (C=O),
138.1 (C), 137.8 (CH), 137.0 (CH), 135.8 (C), 129.9 (C), 124.0
(CH), 123.0 (CH), 118.5 (CH), 118.0 (C), 116.1 (CH2), 115.7 (CH),
115.3 (CH2), 53.5 (CH3), 52.1 (CH2), 42.5 (CH2), 34.3 (CH2), 26.4
(CH2) ppm. HRMS (EI) found: [M+], 298.1681, C18H22N2O2 re-
quires [M+], 298.1669; LRMS (EI): m/z (%) = 299 (9) [MH+], 298
(44), 241 (100).
Ethyl 2-(Allylamino)butyrate: Allylamine (7.7 g, 135 mmol) and
Et3N (13.6 g, 135 mmol) in MeCN (100 mL) was added to ethyl 2-
bromobutyrate (26.4 g, 135 mmol) and the mixture was heated un-
der reflux. After 16 h saturated NaHCO3 (100 mL) was added and
the mixture was extracted with EtOAc (4ϫ50 mL), dried (MgSO4),
filtered and the solvents evaporated. Purification by column
chromatography, eluting with petrol/EtOAc (3:2), gave the amino
ester (18.8 g, 82%) as an oil. Rf = 0.58 [petrol/EtOAc (1:1)]. IR
1
= 3055, 2880, 1730, 1645 cm–1. H NMR (250 MHz,
6-Methyl 1-Allyl-2-ethyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo[3,2-c]-
carbazole-6-carboxylate (22): Sodium 2-(allylamino)butyrate, pre-
pared as described above, (1.11 g, 6.7 mmol) and p-toluenesulfonic
acid (1.03 g, 5.4 mmol) was added to a stirred solution of the alde-
hyde 7 (173 mg, 0.67 mmol) in toluene (50 mL) and the mixture
was heated under reflux. After 16 h, the mixture was filtered
through Celite, washed with CH2Cl2 (25 mL) and the solvents evap-
orated. To this mixture at room temperature in CH2Cl2 (25 mL)
was added pyridine (0.06 mL, 0.67 mmol) and methyl chloro-
formate (0.05 mL, 0.67 mmol). After 16 h the solvent was evapo-
rated and the residue was purified by column chromatography, elut-
ing with CH2Cl2/MeOH (9:1), to give the amine 22 (42 mg, 19%)
(neat): ν
˜
max
CDCl3): δ = 5.68 (ddt, J = 16.5, 10.5, 5.0, = Hz, 1 HCH), 5.06–
4.85 (m, 2 H, H2C=), 4.01 (q, J = 7.0 Hz, 2 H, OCH2), 3.15–2.88
(m, 3 H, CH2 and CH), 1.56–1.41 (m, 2 H, CH2), 1.11 (t, J =
7.0 Hz, 3 H, CH3), 0.77 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR
(63 MHz, CDCl3): δ = 174.6 (C=O), 136.4 (CH), 115.4 (CH2), 61.4
(CH), 59.8 (CH2), 50.3 (CH2), 26.2 (CH2), 13.9 (CH3), 9.6 (CH3)
ppm. HRMS (EI) found: [M+], 171.1259, C9H17NO2 requires [M+],
171.1259; LRMS (ES): m/z (%) = 171 (10) [M+], 99 (100).
Sodium 2-(Allylamino)butyrate: NaOH (1.4 g, 35.5 mmol) was
added to ethyl 2-(allylamino)butyrate (6.1 g, 35.5 mmol) in THF
(10 mL) and H2O (10 mL). After 16 h the solvent was evaporated
to give the title compound (5.2 g, 89%) as a solid; 218–219 °C
as an oil. R = 0.23 [CH Cl /MeOH (95:5)]. IR (neat): νmax = 3075,
˜
f
2
2
1
2930, 2855, 1740, 1640, 1605 cm–1. H NMR (500 MHz, CDCl3):
δ = 8.04–8.01 (m, 1 H, ArH), 7.60–7.54 (m, 1 H, ArH), 7.20–7.15
(m, 2 H, ArH), 5.72 (ddt, J = 17, 10, 6 Hz, 1 H, =CH), 5.03–4.95
(m, 1 H, =CH), 4.93–4.86 (m, 1 H, =CH), 4.22 (d, J = 5 Hz, 1 H,
NCH), 3.94 (s, 3 H, OMe), 3.28 (dd, J = 14, 5.5 Hz, 1 H, CH),
3.13 (dt, J = 18, 4.5 Hz, 1 H, CH), 3.03 (dd, J = 14, 6.5 Hz, 1 H,
CH), 3.00–2.92 (m, 1 H, CH), 2.86–2.72 (m, 1 H, CH), 2.30–2.22
(m, 1 H, CH), 1.84–1.58 (m, 5 H, 5 CH), 1.31–1.20 (m, 1 H, CH),
0.81 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 152.2 (C), 140.6 (C), 135.5 (C), 128.7 (CH), 128.3 (C), 125.1
(CH), 124.8 (CH), 123.7 (C), 120.5 (CH), 115.3 (CH), 109.1 (CH2),
68.1 (CH), 61.6 (CH), 56.0 (CH2), 53.9 (CH3), 36.6 (CH2), 36.2
(CH), 26.1 (CH2), 25.4 (CH2), 24.3 (CH2), 11.0 (CH3) ppm. HRMS
(ES) found: [M+], 338.2002, C21H26N2O2 requires [M+], 338.1994;
LRMS (ES): m/z (%) = 339 (100) [MH+], 242 (61).
(dec.). IR (neat): ν
= 3305, 3075, 2875, 2805, 1640, 1575 cm–1.
˜
max
1H NMR (250 MHz, D2O): δ = 5.81 (ddt, J = 17.0, 10.5, 6.5 Hz,
1 H, =CH), 5.41–5.27 (m, 2 H, H2C=), 3.52–3.28 (m, 3 H, 3ϫCH),
1.84–1.58 (m, 2 H, CH2), 0.87 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C
NMR (90 MHz, D2O): δ = 182.5 (C=O), 135.2 (CH), 117.0 (CH2),
64.1 (CH), 49.6 (CH2), 25.9 (CH2), 9.6 (CH3) ppm. HRMS (ES)
found: [MNa+], 188.0665, C7H12NO2Na2 requires [MNa+],
188.0663; LRMS (ES): m/z (%) = 188 (100) [MNa+], 166 (40)
[MH].
6-Methyl 1-Allyl-2,3,3a,4,5,10c-hexahydro-1H-pyrrolo[3,2-c]carba-
zole-6-carboxylate (20): Sodium (allylamino)acetate, prepared as
described above, (824 mg, 6.0 mmol) and camphorsulfonic acid
(1.5 g, 6.0 mmol) was added to the aldehyde 7 (155 mg, 0.6 mmol)
in toluene (50 mL) and the mixture was heated under reflux. After
5 d, saturated NaHCO3 (20 mL) was added and the mixture was
extracted with CH2Cl2 (4ϫ20 mL), dried (MgSO4), filtered and
the solvents evaporated. Purification by column chromatography,
eluting with CH2Cl2/MeOH (96:4), gave the amine 20 (78 mg, 42%)
Vinyl Sulfone 25: Grubbs’ 2nd generation catalyst (73 mg, 5 mol-%)
was added to the alkene 7 (442 mg, 1.7 mmol) and phenyl vinyl
sulfone (577 mg, 3.4 mmol) in CH2Cl2 (25 mL). The mixture was
heated under reflux for 21 h, then another portion of the catalyst
(73 mg, 5 mol-%) was added and heating continued for a further
as an oil. R = 0.58 [CH Cl /MeOH (96:4)]. IR (neat): νmax = 3070,
˜
f
2
2
2950, 1730, 1605 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.13–8.09 1 h. The solvent was evaporated and the mixture was purified by
(m, 1 H, ArH), 7.58–7.54 (m, 1 H, ArH), 7.26–7.19 (m, 2 H, ArH), column chromatography, eluting with petrol/EtOAc (7:3), to give
5.93–5.84 (m, 1 H, =CH), 5.21 (dd, J = 17.0, 1.0 Hz, 1 H, HC=),
5.05 (d, J = 10.5 Hz, 1 H, HC=), 4.01 (s, 3 H, OCH3), 3.78–3.73
the vinyl sulfone 25 (294 mg, 43%) as an oil; Rf = 0.16 [petrol/
EtOAc (7:3)]. IR (neat): νmax = 3055, 2955, 2920, 2845, 1750, 1660,
˜
2684
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2676–2686

Synthesis of Deethylibophyllidine
FULL PAPER
1
1555, 1385, 1150 cm–1. H NMR (250 MHz, CDCl3): δ = 10.19 (s,
Acknowledgments
1 H, CHO), 8.19–8.10 (m, 1 H, ArH), 7.95–7.87 (m, 1 H, ArH),
7.78–7.70 (m, 2 H, ArH), 7.55–7.35 (m, 3 H, ArH), 7.31–7.23 (m,
2 H, ArH), 6.95 (dt, J = 15.0, 7.5 Hz, 1 H, =CH), 6.31 (d, J =
15.5 Hz, 1 H, =CH), 4.04 (s, 3 H, OCH3), 3.55–3.45 (m, 2 H, CH2),
2.67–2.53 (m, 2 H, CH2) ppm. 13C NMR (63 MHz, CDCl3): δ =
185.4 (C=O), 151.7 (C=O), 149.4 (C), 144.1 (CH), 140.2 (C), 135.3
(C), 133.4 (CH), 132.0 (CH), 129.3 (CH), 127.6 (CH), 126.1 (C),
156.3 (CH), 124.8 (CH), 120.8 (CH), 118.8 (C), 115.5 (CH), 54.6
(CH3), 31.8 (CH2), 24.8 (CH2) ppm. HRMS (ES) found: [MNa+],
420.0863, C21H19NO5NaS requires [MNa+], 420.0882. LRMS (ES):
m/z (%) = 420 (100) [MNa+].
We are grateful to Merck Sharp & Dohme and the University of
Sheffield for support of this work. We thank Harry Adams (Uni-
versity of Sheffield) for the X-ray crystallographic structure analy-
sis. We would like to thank the referees for some helpful comments.
[1] a) W. I. Taylor, in The Alkaloids, Volume XI. Chemistry and
Physiology (Ed.: R. H. F. Manske), Academic Press, New York.
1968, p. 79; b) T. A. Van Beek, M. A. J. T. Van Gessel in Alka-
loids: Chemical and Biological Perspectives (Ed.: S. W. Pel-
letier), Wiley, New York, 1988, vol. 6, p. 75; c) J. E. Saxton in
The Chemistry of Heterocyclic Compounds (Ed.: E. C. Taylor),
Wiley, New York, 1994, supplement to vol. 25, part 4, p. 487.
[2] P. Popik, P. Skolnick in The Alkaloids (Ed.: G. A. Cordell),
Academic Press, New York, 1999, vol. 52, chapter 3, p. 197.
[3] a) F. Khuong-Huu, M. Cesario, J. Guilhem, R. Goutarel, Tet-
rahedron 1976, 32, 2539; b) C. Kan, H.-P. Husson, H. Jacque-
min, S.-K. Kan, M. Lounasmaa, Tetrahedron Lett. 1980, 21,
55.
Cycloadduct Sulfone 26: Sodium (allylamino)acetate, prepared as
described above, (72 mg, 0.52 mmol) and camphorsulfonic acid
(131 mg, 0.52 mmol) was added to the aldehyde 25 (104 mg,
0.26 mmol) in toluene (20 mL) and the mixture was heated under
reflux. After 16 h, the solvent was evaporated and the mixture was
purified by column chromatography, eluting with petrol/EtOAc
(1:1), to give the amine 26 (86 mg, 73%) as an oil. Rf = 0.36 [petrol/
[4] a) M. E. Kuehne, T. H. Matsko, J. C. Bohnert, L. Motyka, D.
Oliver-Smith, J. Org. Chem. 1981, 46, 2002; b) M. E. Kuehne,
J. C. Bohnert, J. Org. Chem. 1981, 46, 3443.
EtOAc (1:1)]. IR (neat): νmax = 3065, 2960, 2920, 2860, 1735, 1605,
˜
1
1460, 1140 cm–1. H NMR (500 MHz, CDCl3): δ = 8.03–7.99 (m,
1 H, ArH), 7.89–7.85 (m, 2 H, ArH), 7.62–7.58 (m, 1 H, ArH),
7.54–7.47 (m, 3 H, ArH), 7.20–7.14 (m, 2 H, ArH), 5.79–5.69 (m,
1 H, =CH), 5.16 (dd, J = 17.0, 0.5 Hz, 1 H, HC=), 5.04–4.98 (m,
1 H, HC=), 3.93 (s, 3 H, OCH3), 3.80 (d, J = 5.0 Hz, 1 H, CH),
3.60 (dd, J = 13.0, 5.5 Hz, 1 H, CH), 3.40–3.35 (m, 1 H, CH), 3.20
(t, J = 10.0 Hz, 1 H, CH), 3.12–3.02 (m, 2 H, 2ϫCH), 2.86–2.76
(m, 2 H, 2ϫCH), 2.74–2.68 (m, 1 H, CH), 2.01–1.91 (m, 1 H, CH),
1.73–1.67 (m, 1 H, CH) ppm. 13C NMR (63 MHz, CDCl3): δ =
152.4 (C=O), 138.6, (C), 137.5 (C), 135.8 (CH), 135.7 (C), 133.8
(CH), 129.7 (C), 129.4 (CH), 128.1 (CH), 123.8 (CH), 122.9 (CH),
118.8 (CH), 117.4 (C, CH2), 114.9 (CH), 66.5 (CH), 59.9 (CH),
58.0 (CH2), 53.5 (CH3), 52.2 (CH2), 38.4 (CH), 26.2 (CH2), 24.2
(CH2) ppm. HRMS (ES) found: [MH+], 451.1677, C25H27N2O4S
requires [MH+], 451.1692. LRMS (ES): m/z (%) = 451 (100) [MH+].
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(9:1)]. H NMR (250 MHz, CDCl3): δ = 8.10–8.06 (m, 1 H, ArH),
7.64–7.60 (m, 1 H, ArH), 7.28–7.20 (m, 2 H, ArH), 4.15 (d, J =
6.0 Hz, 1 H, CH), 4.01 (s, 3 H, OCH3), 3.16–3.07 (m, 2 H, 2ϫCH),
3.03–2.96 (m, 1 H, CH), 2.92–2.84 (m, 1 H, CH), 2.42–2.34 (m, 1
H, CH), 2.16–2.03 (m, 2 H, NH & CH), 1.90–1.83 (m, 1 H, CH),
1.71–1.62 (m, 1 H, CH), 1.62–1.54 (m, 1 H, CH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 152.6 (C=O), 137.0 (C), 135.9 (C), 129.4
(C), 123.8 (CH), 123.0 (CH), 118.6 (CH), 117.8 (C), 115.3 (CH),
54.7 (CH), 53.4 (CH3), 46.1 (CH2), 37.2 (CH), 30.9 (CH2), 26.3
(CH2), 24.1 (CH2) ppm. HRMS (ES) found: [MH+], 271.1439,
C16H19N2O2 requires [MH+], 271.1447; data matches that in the
literature.[7]
Supporting Information (see also the footnote on the first page of
this article): Copies of NMR spectra for compounds 9–11, 14a,
14b, 15a, 15b, 16b, 20–22, 25, 26 and 2.
Eur. J. Org. Chem. 2007, 2676–2686
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2685

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Received: January 19, 2007
Published Online: March 16, 2007
2686
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2676–2686