Synthesis of 1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ones as intermediates for the synthesis of apparicine

Article abstract of DOI:10.3987/COM-10-S(E)5

1-Phenylsulfonylindole is converted in eight steps into 2-(2-iodo-(Z)-but-2-en-1-yl)-6-methyl-1,2,3,4-tetrahydroazocino[4,3-b]indole, previously converted in one step into the indole alkaloid apparicine. The syntheses of other hexahydroazocino[4,3-b]indole potential precursors to the alkaloid are also described. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)5

HETEROCYCLES, Vol. 82, No. 1, 2010
349
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 349 - 370. © The Japan Institute of Heterocyclic Chemistry
Received, 19th January, 2010, Accepted, 18th March, 2010, Published online, 19th March, 2010
DOI: 10.3987/COM-10-S(E)5
SYNTHESIS OF 1,2,3,4,5,7-HEXAHYDRO-6H-AZOCINO[4,3-b]INDOL-
6-ONES AS INTERMEDIATES FOR THE SYNTHESIS OF APPARICINE
Jason G. Kettle, David Roberts, and John A. Joule*
The School of Chemistry, The University of Manchester, Manchester M13 9PL,
UK
Abstract – 1-Phenylsulfonylindole is converted in eight steps into
2-(2-iodo-(Z)-but-2-en-1-yl)-6-methyl-1,2,3,4-tetrahydroazocino[4,3-b]indole,
previously converted in one step into the indole alkaloid apparicine. The syntheses
of other hexahydroazocino[4,3-b]indole potential precursors to the alkaloid are
also described.
INTRODUCTION
The indole alkaloid apparicine emerged from Carl Djerassi’s onslaught on the structures of alkaloids from
South American Aspidosperma species; the paper1 describing its structure determination was already
XLVIII in his series ‘Alkaloid Studies’. Apparicine, named for the Brazilian botanist Apparicio Duarte,
and first isolated from Aspidosperma dasycarpon, was the first of what is now a substantially sized group
of indole alkaloids2 which lack one of the two ethanamine side-chain carbons of biosynthetic precursor
tryptophan, having instead only one carbon between indole C-3 and the basic nitrogen, i.e. apparicine has
a gramine unit and indeed the well-known reactivity of this moiety was utilized in the structural
elucidation.1
N
NMe2
CH2O, Me2NH
AcOH
Me
H
N
H
N
H
N
H
gramine
(–)-apparicine
____________________________________________________________________________________
This paper is dedicated to Prof. Dr. Albert Eschenmoser on the occasion of his 85th birthday.

350
HETEROCYCLES, Vol. 82, No. 1, 2010
This structural parallelism prompted our first approach3 to a synthesis of apparicine since it was known
that gramine is formed easily from indole in a Mannich reaction: the piperidinyl-indolyl-ketal 1 was
constructed via 2-acylation of the Grignard derivative of 4,5,6,7-tetrahydroindole (a pyrrole in reactivity
terms), dehydrogenation to an indole, ketalisation, and reduction of the pyridine ring. Intramolecular
Mannich reaction and hydrolysis of the acetal produced tetracycle 2 with the ring skeleton of apparicine.
H
N
N
CH2O, AcOH, rt
then aq. HCl, rt
35%
N
N
O
O
1
2
O
H
H
Our recent investigations relating to apparicine were not published since we were not able to complete the
total synthesis, however, in 2009, Bennasar et al. described4 the conversion (Scheme 1) of tricycle 3 into
the alkaloid – this key intermediate was one of several with potential for forming the fourth, piperidine
ring, that we had prepared. Our method of construction of this key intermediate and other similar
compounds is now described in this paper; it is completely different to that of the Spanish group, which
was based on ring-closing metathesis to form the eight-membered ring.
Me
I
N
N
N
Pd(OAc)2, Ph3P
Ag2CO3, toluene, Et3N, 80 °C
15%
I
Me
Me
H
N
N
N
Me
H
H
(±)-apparicine
H
3
Me
Scheme 1. Final step in the synthesis4 of apparicine
RESULTS AND DISCUSSION
Since a ring-closing Mannich process had successfully produced tetracycle 2, we determined to retain this
reaction as a key element of a revised strategy in which the goal was to be a
1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one of general form 4. This would have a carbonyl for
eventual conversion into exocyclic methylene and a functionalised N-substituent with potential for
forming the piperidine ring, by a process that perhaps might also involve the ketone. This type of
substance was to be formed via an intramolecular Mannich process but since this requires the absence of
the deactivating carbonyl group, a precursor of the general form 5 was required.

HETEROCYCLES, Vol. 82, No. 1, 2010
351
Me
functionality
N
O
functionality
Me
N
N
N
H
R
H
H OH
5
4
In earlier work,5 1-phenylsulfonylindole was lithiated at C-26 and thus reacted with the imide
1-benzoyl-2-pyrrolidone giving ketone 6. Treatment with lithium aluminium hydride produced
alcohol-amine 7 which closed very satisfactorily under high dilution conditions to 8, thus establishing the
viability of the approach (Scheme 2). However complications7 arose on removal of the N-benzyl group
and we sought a variation that would allow us the flexibility to introduce various functionalized
N-side-chains to a tricyclic compound.
O
N
O
Ph
O
n-BuLi, –78 °C
Li
N
Ph
72%
N
N
N
H
O
O
S
O
O
S
O
6 O
S
O
Ph
Ph
Ph
Ph
N
CH2O, AcOH, rt
(MeOCH2)2, high dilution
LiAlH4
63%
N
H
Ph
96%
N
N
H
H OH
7
8
H
H
OH
Scheme 2
In our first sequence, the whole of the indol-2-yl side-chain of the Mannich substrate was introduced at
once. Reductive amination of crotonaldehyde with 4-aminobutanal diethyl acetal produced amine 9 which
was N-formylated (! 10) before revealing the aldehyde function in 11 using iodotrimethylsilane.
Reaction of the aldehyde with lithium 2-lithioindole-1-carboxylate8 produced alcohol 12 requiring only
formamide hydrolysis (! 13) before Mannich ring closure to 14, manganese dioxide oxidation of the
indolylic alcohol (! 15) and N-protection then producing the ketone 16. An alternative route to alcohol
13 is described later.

352
HETEROCYCLES, Vol. 82, No. 1, 2010
OEt
OEt
H
N
NaBH4
AcOCHO
87%
TMSI
68%
O
Me
NH2
+
Me
10
EtO
EtO
100%
9
H
Li
N
CO2Li
H
CHO
N
Me
+
13
(12%)
N
Me
O
34%
N
CHO
11
12
H
H OH
KOH, EtOH
reflux
12
N
H
Me
60%
N
H
H
OH
13
Me
Me
N
O
N
CH2O, AcOH
(MeOCH2)2, rt, high dilution
MnO2
51%
NaH, PhSO2Cl
67%
15
33%
N
N
H
14
16
H
OH
PhSO2
Scheme 3
O
N
H
PhSO2
46%
17
NaH plus halide
N
Li
N
N
18
PhSO2
O
PhSO2
PhSO2
N
Me
N
Me
N
PhSO2
N
PhSO2
I
O
PhSO2
19
80%
21
95%
Me
23
49%
PhSO2
NaBH4
NaBH4
NaBH4
N
N
Me
N
Me
N
H
OH
PhSO2
Me
PhSO2
I
20
91%
22
76%
24
57%
PhSO2
PhSO2
Scheme 4
This approach required a decision as to which N-side-chain to incorporate, at an early stage, so we
developed an improvement that allows the side-chain unit to be introduced later in the sequence (Scheme

HETEROCYCLES, Vol. 82, No. 1, 2010
353
4). 2-Lithio-1-phenylsulfonylindole was reacted with 1-phenylsulfonyl-2-pyrrolidone 17 generating the
key ketone 18. This, with its acidic sulfonamide N-hydrogen, could be simply N-alkylated under mild
conditions with a variety of halides, and thus were produced 19, 21, and 23. Each of these was simply and
efficiently reduced to the alcohol oxidation level (! 20, 22, and 24) that was to be needed for the
Mannich ring closure.
The removal of phenylsulfonyl N-protection is not always easy and in these intermediates both an
indole-N-phenylsulfonyl and an amine-N-phenylsulfonyl needed to be removed prior to Mannich
cyclisation. Sodium amalgam proved relatively satisfactory (55%) for the conversion of 20 into the
previously prepared butenyl-amine 13. Mg-NH4Cl in methanol9 was an excellent choice for the
conversion of 22 into amine 25 and Mannich closure of this gave the corresponding
alkynyl-azocino-indole 26 in 95% yield, then oxidised (! 27) and N-protected forming ketone 28
(Scheme 5). Application of the Mg-NH4Cl-MeOH method to iodo-butenyl alcohol 24 unfortunately
removed the iodine as well as the phenylsulfonyl groups producing only butenyl-amine 13, once again.
Mg, NH4Cl
MeOH
CH2O, AcOH
(MeOCH2)2, rt
N
N
98%
95%
Me
N
N
H
H
H
OH
H
OH
25
22
PhSO2
Me
PhSO2
Me
Me
N
O
N
MnO2
51%
NaH, PhSO2Cl
67%
27
N
N
26
28
H
OH
H
PhSO2
Scheme 5
Our attention now turned to the missing carbon of the apparicine skeleton – that which is an exocyclic
methylene in the alkaloid. Methyl Grignard addition to the still-protected ketones 19 and 21 proceeded
unexceptionally (! 29, 32), and after removal of the phenylsulfonyl groups, both of the resulting
alcohols 30 and 33, took part in Mannich ring closures very efficiently giving 31 and 34 respectively
(Scheme 6).

354
HETEROCYCLES, Vol. 82, No. 1, 2010
N
Me
N
N
N
PhSO2
PhSO2
Me
O
O
PhSO2
PhSO2
19
21
MeMgCl, THF, rt
93%
MeMgCl, THF, rt
90%
29
32
Na-Hg, Na2HPO4
MeOH, rt
Mg, NH4Cl
MeOH, rt
70%
75%
N
Me
N
N
H
N
H
H
H
Me
OH
Me
OH
30
33
Me
CH2O, AcOH, rt
(MeOCH2)2
high dilution
95%
CH2O, AcOH, rt
(MeOCH2)2
high dilution
88%
Me
Me
N
N
N
N
H
H
31
34
Me OH
Me OH
Scheme 6
It remained to produce an azocino-indole with an iodo-butenyl side-chain (Scheme 7). To this end, we
developed two variants: the alkynyl-alcohol 33 was hydrostannylated giving 35. Although there are no
examples of hydrostannation of propargylamines, we predicted the regiochemistry and stereochemistry of
the hydrostannation based on analogy with the comparable reactions of propargylic alcohols, such as
but-2-ynol, in which the tin attaches to C-2 giving a (Z)-vinylstannane.10 Stannane 35 was then reacted
with iodine, the ipso displacement of tin in a vinylstannane with iodine with retention of configuration
being a well-recognised conversion.10,11 This introduction of iodine was not a clean reaction in the sense
that two products were formed, the desired 36a and a product 36b in which iodination at the indole
3-position had also taken place. Intriguingly, both of these underwent Mannich cyclisation to 37.
Dehydration of this alcohol produced 3, the intermediate which, it was ultimately shown,4 could be
converted in one step into apparicine. The identity of this compound with that produced by the Spanish
route also confirms the regio- and stereochemistry of the hydrostannation. Alternatively, the
alkynyl-azocino-indole 34 could be hydrostannylated (! 38) then converted into iodide 37.

HETEROCYCLES, Vol. 82, No. 1, 2010
355
In conclusion, we have described an efficient route to variously N-substituted
1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ones, utilizing a high-dilution intramolecular Mannich
reaction to form the eight-membered ring; one of these can be converted into apparicine in one step.4 The
precursors for the cyclisation were prepared via the use of 1-phenylsulfonyl-2-pyrrolidone in reaction
with 2-lithio-1-phenylsulfonylindole: this, by selective reaction at the ring carbonyl then ring opening,
generated an indol-2-yl 3-(phenylsulfonylamido)propyl ketone, the acidic N-hydrogen in which was then
used for N-alkylations. This is the first time that 1-phenylsulfonyl-2-pyrrolidone has been used in this
way and seems to offer an efficient general route to ketones of the type R1C(O)(CH2)3NHR2.
R
n-Bu3SnH, AIBN
I2
PhH, reflux
35
42%
N
N
H
Me
N
N
H
Me
OH
Me
H
OH
H
36
a
b
R
33
Me
I
H 23%
I 35%
Me
I
Me
N
N
CH2O, AcOH, rt
(MeOCH2)2, high dilution
n-Bu3SnH, AIBN
I2
PhH, reflux
38
83% from 36a
56% from 36b
65%
Me
36%
N
H
N
H
34
37
Me OH
Me OH
TsOH, PhH, 50 °C
66%
I
N
N
H
3
Me
Scheme 7
EXPERIMENTAL
General
Flash column chromatography was performed using Merck Kieselgel 60 (230-400 mesh) silica.
Tetrahydrofuran (THF) was dried by distillation from sodium-benzophenone; toluene (toluene) and
dichloromethane were dried by distillation from calcium hydride; dimethylformamide was dried over 4 Å
molecular sieves; organic extracts were dried over anhydrous MgSO4. Solutions of n- and t-butyllithium
and methylmagnesium chloride were purchased from the Aldrich chemical company and used without
titration. UV spectra were recorded on a Shimadzu-260 UV-VIS recording spectrophotometer at fast scan
speed, path length 1 cm in EtOH solution. IR spectra were recorded on a Perkin-Elmer 1710 Infra Red
1
Fourier transform spectrometer as films. H NMR spectra were recorded on a Varian AC 300E NMR

356
HETEROCYCLES, Vol. 82, No. 1, 2010
spectrometer operating at 300 MHz or a Varian Gemini 200 spectrometer operating at 200 MHz.
Chemical shifts are reported in parts per million downfield from tetramethylsilane. Peak multiplicities are
denoted by s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet) and m
13
(multiplet) or by a combination of these e.g. dd (double doublet). C NMR spectra were recorded on a
Varian AC 300E NMR spectrometer at 75 MHz. Mass spectra were recorded on a Kratos MS 25
spectrometer. The modes of ionisation used are indicated as follows: electron impact (EI), chemical
ionisation (CI) and fast atom bombardment (FAB). Accurate mass measurements were recorded on a
Kratos concept. All reactions were carried out under a dry atmosphere of nitrogen or argon unless
otherwise stated.
4-(N-(E-but-2-en-1-yl)amino)butanal diethyl acetal 9. 4-Aminobutanal diethyl acetal (10.0 mL, 11.6
mmol) and but-2-enal (10.0 mL, 24.4 mmol) were stirred in EtOH (150 mL) at 0 °C for 3 h. The reaction
mixture was concentrated in vacuo then EtOH (100 mL) added. The solution was cooled to 0 °C and
NaBH4 (1.0 g, 23.3 mmol) added slowly. The mixture was allowed to come to rt and after 3 h, H2O (50
mL) was added and the organic solvent evaporated. The product was extracted with Et2O, the extract
dried filtered and concentrated leaving the amine 9 as a yellow oil (12.4 g, 100%), showing a single spot
on tlc (toluene:EtOAc, 1:1 plus 1% Et3N) and used as such for the next step, "max 3312, 2974, 2931, 1673
cm–1, #H (CDCl3, 200 MHz) 5.53 (2H, m, NCH=CH), 4.46 (1H, t, J = 5 Hz, OCHO), 3.53 (4H, m,
2xOCH2), 3.12 (2H, d, J = 5 Hz, NCH2C=C), 2.57 (2H, m, CH2CH2N), 1.64 (3H, d, J = 5 Hz, CH3C=C),
1.57 (4H, m, CHCH2CH2), 1.17 (6H, t, J = 6.5 Hz, 2xCH3); m/z (CI) 216 (MH+, 39%), 186 (9), 170 (17),
124 (19), 84 (20); C12H25NO2 requires 215.1885. Found 215.1884.
4-(N-(E-but-2-en-1-yl)formamido)butanal diethyl acetal 10. To a stirred solution of acetic formic
anhydride (1.4 g, 16.0 mmol) in dry THF (20 mL) at –70 °C was added 4-(N-(E-but-2-en-1-
ylamino)butanal diethyl acetal 9 (2.87 g, 13.0 mmol) in THF (5 mL). The mixture was allowed to reach rt
then stirred for 18 h. After concentration in vacuo, the residue was partitioned between Et2O (20 mL) and
H2O (20 mL), the layers separated and the aqueous layer re-extracted with Et2O (2x20 mL). The
combined organic extracts were dried, filtered and evaporated leaving a red oil which was purified by
chromatography over silica (toluene:EtOAc, 1:1) giving the formamide 10 as an orange oil (2.82 g, 87%),
"
2973, 1669 cm–1; #H (CDCl3, 200 MHz) 8.05 (1H, s, CH=O), 5.65 (1H, m, HC=C), 5.33 (1H, m,
max
C=CH), 4.48 (1H, m, OCHO), 3.87 (1H, d, J = 6 Hz, one of NCH2C=C), 3.75 (1H, d, J = 6 Hz, one of
NCH2C=C), 3.54 (4H, m, 2xCH2CH3), 3.25 (2H, m, CH2CH2N), 1.71 (2H, m, two of CH2CH2), 1.58 (11H,
m, two of CH2CH2 plus 3xCH3); m/z (FAB) 243 (M+, 3%), 198 (100), 144 (15), 98 (40); C13H25NO3
–C2H5OH requires 198.1480. Found 198.1494.

HETEROCYCLES, Vol. 82, No. 1, 2010
357
4-(N-(E-But-2-en-1-yl)formamido)butanal 11. To a stirred solution of 4-(N-(E-but-2-en-1-yl)-
formamido)butanal diethyl acetal 10 (9.37 g, 39.0 mmol) in dry CH2Cl2 (100 mL) at rt was added
iodotrimethylsilane (6.44 mL, 43.0 mmol) dropwise to give a deep red solution. Stirring was continued
for 30 min, the reaction mixture washed with aq Na2S2O3 (100 mL, 1M) and dried. Concentration gave an
orange oil which was purified by chromatography over silica (toluene:EtOAc, 1:1) to give the aldehyde
11 as an orange oil (4.45 g, 68%), "max 2937, 1722, 1668 cm–1; #H (CDCl3, 200 MHz) 9.80 (1H, m,
CH2CH=O), 8.05 (1H, s, NCH=O), 5.66 (1H, m, HC=C), 5.36 (1H, m, C=CH), 3.85 (1H, d, J = 6 Hz, one
of NCH2C=C), 3.75 (1H, d, J = 6 Hz, one of NCH2C=C), 3.27 (1H, t, J = 6 Hz, one of NCH2CH2), 3.24
(1H, t, J = 6 Hz, one of NCH2CH2), 2.50 (2H, m, CH2C=O), 1.86 (2H, m, CH2CH2CH2), 1.75 (3H, d, J = 6
Hz, CH3); m/z (CI) 170 (MH+, 100%); C9H15NO2 requires 169.1103. Found 169.1104.
4-(N-(E-But-2-en-1-yl)formamido)-1-(indol-2-yl)butan-1-ol 12. To a stirred solution of indole (0.41 g,
3.5 mmol) in dry THF (10 mL) at –70 °C was added n-butyllithium (1.6 M solution in hexane, 2.39 mL,
3.8 mmol). The resulting suspension was held at –70 °C for 30 minutes, then CO2 bubbled through to give
a colourless solution, which was stirred for a further 10 min. The solvent was removed in vacuo (< 10 °C)
to give a white crystalline solid that was redissolved in THF (10 mL). The solution was recooled to
–70 °C and t-butyllithium (1.7 M solution in pentane, 5.77 mL, 3.8 mmol) added slowly to give a bright
yellow solution which was stirred for 1 h at –70 °C. A solution of 4-(N-(E-but-2-en-1-yl)-
formamido)butanal 11 (0.59 g, 3.5 mmol) in THF (5 mL) was added dropwise, the reaction mixture
stirred for a further hour at –70 °C and subsequently allowed to warm to rt. The solution was poured into
saturated aq NH4Cl (30 mL), and extracted into Et2O (2 x 20 mL). The combined organic extracts were
dried and concentrated to give a brown oil which was purified by chromatography (EtOAc) to give the
alcohol 12 as an orange oil (0.34 g, 34%), $max (log %max) 220 (4.14), 271 (3.75), 279 (3.74), 2.88 (3.63);
"
max 3298, 2934, 1654 cm–1; #H (CDCl3, 300 MHz) 8.82 (1H, bs, indol-1-yl-H), 8.00 (1H, s, CH=O), 7.56
(1H, d, J = 7.5 Hz, ArH), 7.38 (1H, d, J = 7.5 Hz, ArH), 7.15 (2H, m, ArH), 6.33 (1H, s, indol-3-yl-H),
5.62 (1H, m, HC=C), 5.36 (1H, m, C=CH), 4.92 (1H, t, J = 7 Hz, CHOH), 3.83 (1H, d, J = 7 Hz, one of
NCH2C=C), 3.66 (1H, d, J = 7 Hz, one of NCH2C=C), 3.34 (1H, t, J = 7 Hz, one of NCH2CH2), 3.14 (1H,
t, J = 7 Hz, one of NCH2CH2), 1.86 (2H, quint, J = 7 Hz, CH2CH2CH2), 1.67 (5H, m+d, NCH2CH2CH2
plus C=CCH3); m/z (CI) 286 (M+, 6%), 269 (78), 170 (53), 158 (23), 146 (27), 118 (60), 102 (48), 100
(61), 84 (33). Further elution (EtOH:Et3N, 99:1) gave amine 13 (0.112 g, 12%) (see below for
characterisation).
4-(E-But-2-en-1-ylamino)-1-(indol-2-yl)butan-1-ol 13. Method (a): 4-(N-(E-But-2-en-1-yl)formamido)-
1-(indol-2-yl)butan-1-ol 12 (0.28 g, 1.0 mmol) and potassium hydroxide (1 g) were heated at reflux in

358
HETEROCYCLES, Vol. 82, No. 1, 2010
ethanol (15 mL) for 2 h. The reaction mixture was poured into water (50 mL) and product extracted into
EtOAc (2 x 30 mL). The combined organic extracts were dried and concentrated to give a brown oil
which was purified by chromatography (EtOH:Et3N, 99:1) to give the amine 13 as waxy solid (0.15 g,
60%), $max (log %max) 218 (4.07), 271 (3.78), 280 (3.78), 288 (3.68); "max 3500, 3285, 2935 cm–1; #H
(CDCl3, 200 MHz) 8.87 (1H, bs, indol-1-yl-H), 7.58 (1H, d, J = 7.5 Hz, ArH), 7.38 (1H, d, J = 7.5 Hz,
ArH), 7.16 (1H, apparent t, J = 7.5 Hz, ArH), 7.10 (1H, apparent t, J = 7.5 Hz, ArH), 6.27 (1H, s,
indol-3-yl-H), 5.61 (2H, m, HC=CH), 4.96 (1H, dd, J = 7.5, 2.3, Hz, CHOH), 4.22 (2H, bs, OH plus NH),
3.20 (2H, d, J = 7.5 Hz, NCH2C=C), 2.76 (1H, m, one of NCH2CH2), 2.63 (1H, m, one of NCH2CH2),
2.18 (1H, m, one of CH2CH2CH2), 2.03 (1H, m, one of CH2CH2CH2), 1.88 (1H, m, one of CH2CH2CH2),
1.74 (4H, d+m, one of CH2CH2CH2 plus CH3); m/z (CI) 259 (MH+, 100%), 241 (80); C16H22N2O requires
258.1732. Found 258.1729.
Method (b): To a stirred solution of 4-(N-(E-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonyl-
indol-2-yl)butan-1-ol 20 (1.0 g, 1.9 mmol) and Na2HPO4 (2.6 g, 7.0 mmol) in dry MeOH (50 mL) at rt
was added 6% sodium amalgam (10 g) gradually. Stirring was continued for 5 h, then the solution
decanted from the residues, concentrated and partitioned between water (50 mL) and CH2Cl2 (50 mL).
The aqueous layer was washed with CH2Cl2 (2 x 30 mL) and the combined organic extracts dried.
Concentration gave a brown oil which was purified by chromatography (toluene:EtOAc:EtOH, 1:1:1) to
give the amine 13 as a colourless waxy solid (0.266 g, 55%).
2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 14. Formalin (1.75 mL, 40%)
and AcOH (1.75 mL) were added to a stirred solution of 4-(E-but-2-en-1-ylamino)-1-
(indol-2-yl)butan-1-ol 13 (0.16 g, 0.6 mmol) in glyme (75 mL). After 30 min at rt the solution was
concentrated in vacuo to ~3 mL then aq NaOH (10 mL, 3M) and Et2O (10 mL) were added and the layers
separated. The aqueous phase was extracted twice more with Et2O, the combined extracts dried, filtered
and evaporated leaving an oil (0.185 g) which was purified by chromatography over silica
(toluene:EtOAc, 1:1 plus 1% Et3N) giving the tricycle 14 as an orange oil (56 mg, 33%), $max (log %max)
223 (4.02), 274 (3.90), 281 (3.92), 289 (3.89); "max 3398, 3222, 2918, 2854 cm–1; #H (CDCl3+D2O, 300
MHz) 7.54 (1H, d, J = 8.3 Hz, ArH), 7.35 (1H, d, J = 8.3 Hz, ArH), 7.20 (1H, t, J = 8.3 Hz, ArH), 7.13
(1H, t, J = 9 Hz, ArH), 5.70 (2H, m, CH=CH), 4.90 (1H, t, J = 3.8 Hz, CHO), 4.20 (1H, d, J = 15.8 Hz,
one of ArCH2N), 3.16 (1H, d, J = 15.6 Hz, one of ArCH2N), 3.38 (1H, m, one of NCH2C=C), 3.27 (1H, m,
one of NCH2C=C), 2.90 (1H, m, one of CH2CH2N), 2.59 (1H, m, one of CH2CH2N), 2.07 (1H, m, one of
CH2CH2), 1.94 (2H, m, two of CH2CH2), 1.75 (4H, d+m, J = 7.5 Hz, one of CH2CH2 plus CH3); m/z (CI)
271 (MH+, 100%), 253 (38), 173 (33), 84 (30), 70 (25), 70 (25); C17H22N2O requires 270.1732. Found
270.1729.

HETEROCYCLES, Vol. 82, No. 1, 2010
359
2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 15. To a stirred solution of
2-(E-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 14 (0.47 g, 1.7 mmol) in CH2Cl2
(100 mL) at rt was added MnO2 (1.5 g). The resulting suspension was stirred for 72 h and then the solid
filtered off and washed with CH2Cl2. Concentration of the solution gave a brown solid which was purified
by chromatography (EtOAc:EtOH, 9:1). This gave the ketone 15 as a white crystalline solid (0.235 g,
51%), mp 139-141 °C, $max (log %max) 206 (4.26), 225 (3.98), 313 (4.12); "max 3329, 2918, 2812, 1629
cm–1; #H (CDCl3, 300 MHz) 9.10 (1H, bs, indol-1-yl-H), 7.67 (1H, d, J = 8.0 Hz, ArH), 7.40 (1H, d, J = 8
Hz, ArH), 7.38 (1H, t, J = 8 Hz, ArH), 7.19 (1H, t, J = 8.0 Hz, ArH), 5.54 (2H, bs, HC=CH), 4.45 (2H, bs,
indol-3-ylCH2N), 3.08 (4H, m, NCH2C=C plus NCH2CH2), 2.65 (2H, m, CH2C=O), 2.10 (2H, m,
NCH2CH2CH2), 1.71 (3H, d, J = 7.5 Hz, CH3); m/z (EI) 268 (M+, 100%), 213 (38), 185 (33), 170 (15),
157 (76), 143 (24), 129 (100), 110 (40), 84 (55); C17H20N2O requires C, 76.1; H, 7.5; N, 10.4%. Found C,
76.4; H, 7.6; N, 10.4%.
2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-7-phenylsulfonyl-6H-azocino[4,3-b]indol-6-one 16. To a
stirred solution of 2-(E-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 15 (0.88 g,
3.3 mmol) in dry DMF (50 mL) at rt was added NaH (60% dispersion in mineral oil, 0.144 g, 3.6 mmol).
The solution was stirred until the evolution of H2 had ceased (ca. 1 h), then PhSO2Cl (0.46 mL, 3.6 mmol)
was added dropwise. Stirring continued for a further 1 h and then the reaction mixture was poured into
water (100 mL) and product extracted into CH2Cl2 (2 x 40 mL). The combined organic extracts were
dried and concentrated to give a brown oil which was purified by chromatography using (toluene:EtOAc,
99:1) to give N-phenylsulfonyl-ketone 16 as a yellow oil (0.9 g, 67%), $max (log %max) 220 (4.26); "max 2932,
1688 cm–1; #H (CDCl3, 300 MHz) 8.16 (2H, d, J = 8.0 Hz, ArH), 7.98 (1H, d, J = 8.0 Hz, indol-7-yl-H),
7.60-7.28 (6H, m, ArH), 5.50 (2H, m, HC=CH), 3.72 (2H, s, indol-3-ylCH2N), 3.13 (2H, d, J = 5.5 Hz,
NCH2C=C), 2.74 (4H, m, CH2CH2CH2), 2.00 (2H, m, CH2CH2CH2), 1.65 (3H, d, J = 5.5 Hz, CH3); m/z
(CI) 409 (MH+, 100%), 269 (36), 267 (40), 160 (23), 94 (31); C23H25N2O3S requires 409.1586. Found
409.1577.
1-Phenylsulfonyl-2-pyrrolidone 17. Method (a). To a stirred solution of 2-pyrrolidone (20.0 g, 0.24 mol),
n-Bu4NHSO4 (0.5 g, 1.5 mmol) and powdered NaOH (20.0 g, 0.5 mol) in dry CH2Cl2 (1 L) at 0 °C was
added PhSO2Cl (33 mL, 45.3 g, 0.26 mol). The suspension was stirred for 18 h then poured into water (1
L). The organic layer was separated and the aqueous layer washed with CH2Cl2 (2 x 200 mL). The
combined organic extracts were dried then concentration gave an orange oil which yielded the
sulfonamide 17 as a white crystalline solid upon trituration with ethanol (11.90 g, 22%, mp 79-81 °C),
"
max 2985, 1739 cm–1; #H (CDCl3, 200 MHz) 8.02 (2H, d, J = 8 Hz, H-2',6'), 7.70-7.48 (3H, m, H-3',4',5'),

360
HETEROCYCLES, Vol. 82, No. 1, 2010
3.93 (2H, t, J = 8 Hz, NCH2), 2.12 (2H, t, J = 8 Hz, CH2C=O), 2.03 (2H, quint, J = 8 Hz, CH2CH2CH2);
m/z (EI) 226 (MH+, 18%), 161 (100), 141 (20), 106 (72), 77 (90); C10H12NO3S requires 226.0538; Found
226.0529.
Method (b). To a stirred solution of 2-pyrrolidone (5 g, 6 mmol) in THF (150 mL) NaH (2.6 g, 60%
dispersion in mineral oil, 6.6 mmol) was added carefully. The solution was stirred until the evolution of
hydrogen had ceased (ca. 1 h), then PhSO2Cl (8.25 mL, 6.6 mmol) was added dropwise. Stirring was
continued for a further 1 h then the reaction mixture was poured into water (200 mL) and product
extracted into CH2Cl2 (2 x 100 mL). The combined organic extracts were dried and concentrated to give a
brown oil which was purified by chromatography (toluene:EtOAc, 9:1) giving the sulfonamide 17 as
white needles (5.42 g, 41%). All spectra as in Method (a).
4-Phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18. To a stirred solution of
1-phenylsulfonylindole (20.0 g, 78.0 mmol) in dry THF (2 L) at –70 °C was added n-BuLi (1.6 M
solution in hexane, 53.5 mL, 86.0 mmol) dropwise. The reaction mixture was allowed to rise to 0 °C over
30 min to give
a
deep orange solution which was then recooled to –70 °C.
1-Phenylsulfonyl-2-pyrrolidone 17 (17.5 g, 78.0 mmol) in THF (100 mL) was added dropwise and the
solution allowed to rise to rt. Water (50 mL) was added and the reaction mixture concentrated in vacuo to
ca. 50 mL. The solution was poured into saturated aq NH4Cl (150 mL), and extracted into Et2O (2 x 100
mL). The combined organic extracts were dried and concentrated to give a brown oil which was purified
by chromatography using (toluene:EtOAc, 19:1!4:1) to give the ketone 18 as a pale brown crystalline
solid (17.32 g, 46%), then triturated with EtOH, mp 111-113 °C; $max (log %max) 216 (5.26), 273 (5.11),
281 (5.11); "max 3291, 2936, 1690 cm–1; #H (CDCl3, 200 MHz) 8.14 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.92
(2H, d, J = 7.5 Hz, ArH) 7.60-7.20 (11H, m, ArH), 7.09 (1H, s, indol-3-yl-H), 4.82 (1H, bs, NH), 3.10
(4H, m, CH2CH2CH2), 2.00 (2H, quint, J = 7.5 Hz, CH2CH2CH2); #C (CDCl3, 75 MHz) 194.1 (s), 139.9
(s), 139.3 (s), 138.5 (s), 137.9 (s), 134.0 (d), 132.6 (d), 129.1 (d), 129.0 (d), 128.5 (s), 127.6 (d), 127.3 (d),
127.0 (d), 124.5 (d), 123.0 (d), 117.0 (d), 115.6 (d), 42.4 (t), 39.1 (t), 24.1 (t); m/z (CI) 500 (MNH4+,
100%), 483 (MH+, 4), 360 (87), 343 (38), 327 (36), 243 (53), 185 (42), 160 (71); C24H22N2O5S2 + NH4
requires 500.1314. Found 500.1311.
4-(N-(E-But-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 19. To a
stirred solution of 4-phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18 (1.94 g, 4.0
mmol) in dry DMF (100 mL) at rt was added NaH (60% dispersion in mineral oil, 0.161 g, 4.0 mmol).
The solution was stirred until the evolution of H2 had ceased (ca. 1 h) then crotyl bromide (0.5 mL, 4.0
mmol) was added dropwise. Stirring continued for a further 1 h and then the reaction mixture was poured

HETEROCYCLES, Vol. 82, No. 1, 2010
361
into water (100 mL) and extracted into CH2Cl2 (2 x 40 mL). The combined organic extracts were dried
and concentrated to give a brown oil which was purified by chromatography (toluene:EtOAc, 99:1) to
give the ketone 19 as a white crystalline solid (1.72 g, 80%) mp 95-97 °C; $max (log %max) 207 (4.29), 273
(4.12), 281 (4.11); "max 2936, 1690 cm–1; #H (CDCl3, 300 MHz) 8.10 (1H, d, J = 7.5 Hz, indol-7-yl-H),
7.95 (2H, d, J = 7.5 Hz, ArH), 7.80 (2H, d, J=7.5 Hz, ArH), 7.60-7.27 (9H, m, ArH), 7.15 (1H, s,
indol-3-yl-H), 5.61 (1H, m, HC=C), 5.23 (1H, m, C=CH), 3.79 (2H, d, J = 6.0 Hz, NCH2C=C), 3.25 (2H,
t, J = 6.0 Hz, NCH2CH2), 3.03 (2H, t, J = 6 Hz, CH2C=O), 2.00 (2H, quint, J = 6 Hz, CH2CH2CH2), 1.60
(3H, s, CH3); m/z (CI) 554 (MNH4+, 100%), 537 (MH+, 12%), 414 (37), 257 (17), 177 (38), 160 (44);
C28H28N2O5S2 requires C, 62.7; H, 5.2; N, 5.3; S, 11.9%. Found C, 62.9; H, 5.2; N, 5.3; S, 12.2%.
4-((N-But-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 21. In a similar
manner, 4-phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18 (9.68 g, 20.0 mmol), NaH
(60% dispersion in mineral oil, 0.8 g, 20.0 mmol) and bromobut-2-yne (2.57 g, 20.0 mmol) in DMF (500
mL) afforded a brown oil which was purified by chromatography (toluene:EtOAc, 99:1) to give ketone 21
as a white crystalline solid (10.72 g, 100%) mp 121-123 °C; $max (log %max) 217 (4.67), 285 (4.36); "max
3066, 2921, 1691 cm–1; #H (CDCl3, 300 MHz) 8.15 (1H, d, J = 7.5 Hz, indol-7-yl-H), 8.03 (2H, d, J = 7.5
Hz, ArH), 7.88 (2H, d, J = 7.5 Hz, ArH), 7.66-7.34 (9H, m, ArH), 7.18 (1H, s, indol-3-yl-H), 4.12 (2H, q,
J = 1.5 Hz, &CH2C'C), 3.34 (2H, t, J = 7.5 Hz, NCH2CH2), 3.12 (2H, t, J = 7.5 Hz, CH2C=O), 2.10 (2H,
quint, J = 7.5 Hz, CH2CH2CH2), 1.58 (3H, t, J = 1.5 Hz, CH3); #C (CDCl3, 75 MHz) 194.0 (s), 139.4 (s),
138.9 (s), 138.6 (s), 138.3 (s), 133.8 (d), 132.6 (d), 120.1 (s), 128.9 (s), 128.7 (s), 128.5 (d), 127.8 (d),
127.5 (d), 127.4 (d), 124.4 (d), 122.9 (d), 116.8 (d), 115.5 (d), 81.9 (s), 71.5 (s), 45.6 (t), 39.1 (t), 36.9 (t),
21.8 (t), 3.3 (q); m/z (CI) 535 (MH+, 40%), 395 (42), 160 (100); C28H27N2O5S2 requires 535.1361. Found
535.1366.
4-(N-(2-Iodo-Z-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 23. In
a similar manner, 4-phenylsulfonylamido-1-(1-phenylsulfonylindol-2-yl)butan-1-one 18 (12.0 g, 25.0
mmol), NaH (60% dispersion in mineral oil, 1.0 g, 27.0 mmol) and 1-bromo-2-iodo-Z-but-2-ene (6.5 g,
25.0 mmol) in DMF (500 mL) afforded a brown oil which was purified using chromatography
(toluene:EtOAc, 99:1) to give the ketone 23 as a white crystalline solid (8.0 g, 49%) mp 131-132 °C, $max
(log %max) 219 (5.03), 271 (4.56), 284 (4.57); "max 3063, 2928, 2875, 1690 cm–1; #H (CDCl3, 300 MHz)
8.15 (1H, d, J = 7.5 Hz, indol-7-yl-H), 8.00 (2H, d, J = 7.5 Hz, ArH), 7.86 (2H, d, J = 7.5 Hz, ArH),
7.64-7.31 (9H, m, ArH), 7.14 (1H, s, indol-3-yl-H), 5.96 (1H, q, J = 6.8 Hz, C=CH), 4.15 (2H, s,
NCH2C=C), 3.33 (2H, t, J = 7.5 Hz, NCH2CH2), 3.04 (2H, t, J = 7.5 Hz, CH2C=O), 2.02 (2H, quint, J =
7.5 Hz, CH2CH2CH2), 1.76 (3H, d, J = 6.8 Hz, CH3); m/z (CI) 680 (MNH4+, 18%), 497 (22), 177 (23), 160

362
HETEROCYCLES, Vol. 82, No. 1, 2010
(100); C28H27IN2O5S2 + NH4 requires 680.0750; Found 680.0781.
4-(N-(E-But-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 20. To a stirred
solution of 4-(N-(E-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 19
(0.115 g, 0.2 mmol) in absolute ethanol (10 mL) at rt was added sodium borohydride (20 mg, 0.4 mmol).
The solution was stirred for 3 h, water (2 mL) added, and stirring continued for a further 2 h. The solvent
was removed in vacuo and the residue partitioned between water (10 mL) and CH2Cl2 (10 mL). The
aqueous phase was re-extracted with CH2Cl2 (2 x 20 mL) and the combined organic extracts dried.
Concentration gave an orange oil which was purified by chromatography (toluene:EtOAc, 85:15) to give
the alcohol 20 as a colourless oil (0.105 g, 91%), $max (log %max) 204 (4.74), 255 (4.60); "max 3509, 2921
cm–1; #H (CDCl3, 300 MHz) 8.15 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.81 (4H, m, ArH), 7.58-7.17 (9H, m,
ArH), 6.69 (1H, s, indol-3-yl-H), 5.60 (1H, m, HC=C), 5.22 (2H, m, C=CH plus CHOH), 3.78 (2H, d, J =
6 Hz, NCH2C=C), 3.23 (2H, t, J = 7 Hz, NCH2CH2), 2.05-1.70 (4H, m, NCH2CH2CH2), 1.60 (3H, d, J = 6
Hz, CH3); m/z (CI) 538 (M+, 6%), 521 (27), 399 (47), 160 (100); C28H30N2O5S2 + NH4 requires 556.1940.
Found 556.1954.
4-(N-(But-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 22. In a similar
manner, 4-([N-but-2-ynyl]phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 21 (3.28 g,
6.1 mmol) and sodium borohydride (0.57 g, 14.0 mmol) in ethanol (200 mL) afforded a yellow oil which
was purified by chromatography (toluene:EtOAc, 85:15) to give the alcohol 22 as a white crystalline
solid (2.49 g, 76%) mp 131.5-133 °C, $max (log %max) 210 (5.59), 244 (4.91); "max 3529, 3067, 2921, 2871,
2226 cm–1; #H (CDCl3, 300 MHz) 8.14 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.90 (2H, d, J = 7.5 Hz, ArH),
7.84 (2H, d, J = 7.5 Hz, ArH), 7.60-7.25 (9H, m, ArH), 6.73 (1H, s, indol-3-yl-H), 5.30 (1H, m, CHOH),
4.13 (2H, s, NCH2C'C), 3.37 (2H, m, NCH2CH2), 2.12 (2H, m, CH2CHOH), 1.90 (2H, m, CH2CH2CH2),
1.55 (3H, s, CH3); m/z (CI) 554 (MNH4+, 2%), 536 (M+, 1%), 519 (5), 239 (15), 160 (100), 118 (27);
C28H28N2O5S2 requires C, 62.7; H, 5.2; N, 5.2; S, 11.9%. Found C, 62.5; H, 5.3; N, 5.3; S, 12.2%.
4-(N-(2-Iodo-(Z)-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 24. In
a similar manner, 4-(N-(2-Iodo-(Z-)-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)-
butan-1-one 23 (8.0 g, 12.0 mmol) and sodium borohydride (1.0 g, 27.0 mmol) in ethanol (500 mL)
afforded a yellow oil which was purified by chromatography (toluene:EtOAc, 85:15) to give the alcohol
24 as a colourless oil (4.55 g, 57%), $max (log %max) 216 (5.18), 248 (4.70), 290sh (4.07); "max 3528, 2924
cm–1; #H (CDCl3, 300 MHz) 8.14 (1H, d, J = 7.5 Hz, indol-7-yl-H), 7.86 (2H, d, J = 7.5 Hz, ArH), 7.83
(2H, d, J = 7.5 Hz, ArH), 7.61-7.19 (9H, m, ArH), 6.70 (1H, s, indol-3-yl-H), 5.95 (1H, q, J = 7.5 Hz,

HETEROCYCLES, Vol. 82, No. 1, 2010
363
C=CH), 5.68 (1H, m, CHOH), 4.13 (2H, s, NCH2C=C), 3.34 (2H, t, J = 7.5 Hz, NCH2CH2), 2.00 (2H, m,
NCH2CH2CH2), 1.78 (5H, d+m, CH2CH2CH2 plus CH3); m/z (CI) 664 (M+, 30%), 647 (20), 497 (32), 469
(22), 371 (19), 355 (35), 160 (100); C28H29IN2O5S2 + NH4 requires 682.0892. Found 682.0892.
4-(But-2-ynylamino)-1-(indol-2-yl)butan-1-ol 25. Method A. To
a
stirred solution of
4-(N-(but-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)butan-1-ol 23 (0.42 g, 0.8 mmol),
Na2HPO4 (0.433 g, 3.0 mmol) in dry MeOH (50 mL), 6% sodium amalgam (10 g) was added gradually.
After 5 h stirring, the solution was decanted off, solvent evaporated and the residue partitioned between
water (40 mL) and CH2Cl2 (40 mL). The dried organic extract was evaporated and the residue purified by
chromatography giving the alcohol 25 as a white crystalline solid (0.158 g, 75%), mp 94-95 °C, $max (log
%max) 218 (4.62), 265 (4.00), 280 (3.97), 288 (3.87); "max 3287, 2918, 2855 cm–1; #H (CDCl3, 300 MHz)
8.83 (1H, bs, indol-1-yl-H), 7.60 (1H, d, J = 7.5 Hz, ArH), 7.40 (1H, d, J = 7.5 Hz, ArH), 7.19 (1H, t, J =
7.5 Hz, ArH), 7.13 (1H, t, J = 7.5 Hz, ArH), 6.29 (1H, s, indol-3-yl-H), 4.98 (1H, m, CHOH), 4.19 (2H,
bs, OH plus NH), 3.40 (2H, m, NCH2C'C), 2.90 (1H, m, one of NCH2CH2), 2.73 (1H, m, one of
NCH2CH2), 2.17 (1H, m, one of NCH2CH2CH2), 2.07 (1H, m, one of NCH2CH2CH2), 1.88 (4H, m+s, one
+
of NCH2CH2CH2 plus CH3), 1.75 (1H, m, one of NCH2CH2CH2); m/z (CI) 257 (MH , 70%), 239 (100%).
(MM 257.1654. C H N O requires 257.1654).
16 21 2
Method B. A suspension of magnesium (10 g, 0.42 mol) and ammonium chloride (0.19 mol) in dry
MeOH (500 mL) containing 4-(N-(but-2-ynyl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)-
butan-1-ol 22 (5.41 g, 10.0 mmol) was vigourously stirred for 2 h, then water (100 mL) added and the
reaction mixture concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL), washed with
water (50 mL) and dried. Concentration gave a pale brown crystalline solid that was purified by
chromatography to give the alcohol 25 as a white crystalline solid (2.63 g, 98%). All spectra were
identical to those given above.
2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 26. To a stirred solution of
4-(but-2-ynylamino)-1-(indol-2-yl)butan-1-ol 25 (0.73 g, 2.9 mmol) in 1,2-dimethoxyethane (1 L) at rt
was added formalin (8 mL, 40%) and AcOH (8 mL). After 30 min the solution was concentrated in vacuo
to ca. 5 mL and aqueous NaOH (20 mL) and Et2O (20 mL) were added. The aqueous phase was
re-extracted with Et2O (2 x 20 mL) and the combined organic extracts dried. Concentration gave a brown
oil which was purified by chromatography (toluene:EtOAc:EtOH. 2:2:1). This gave the azocino-indole 26
as a colourless oil (0.76 g, 95%), $max (log %max) 223 (4.56), 274 (4.35), 288sh (4.24); "max 3396, 3225,
3056, 2918 cm–1; #H (CDCl3, 300 MHz) 8.28 (1H, bs, indol-1-yl-H), 7.51 (1H, d, J = 7.5 Hz, ArH),
7.35-7.12 (3H, m, ArH), 4.90 (1H, m, CHOH), 4.16 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.90 (1H,

364
HETEROCYCLES, Vol. 82, No. 1, 2010
d, J = 15 Hz, one of indol-3-ylCH2N), 3.60 (2H, m, NCH2C'C), 2.82 (2H, t, J = 6 Hz, NCH2CH2),
2.10-1.75 (4H, m, NCH2CH2CH2), 1.90 (3H, t, J = 1.8 Hz, CH3); m/z (CI) 269 (MH+, 100%), 196 (12);
C17H20N2O requires 268.1576; Found 268.1582.
2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 27. A mixture of 2-(but-2-ynyl)-
1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-ol 26 (0.77 g, 2.9 mmol) and manganese dioxide (2.5 g)
was stirred in CH2Cl2 (50 mL) at rt for 72 h. Filtration and evaporation afforded a brown solid which was
purified by chromatography (EtOAc). This gave the ketone 27 as a white crystalline solid (0.18 g, 23%),
mp 162-163 °C, $max (log %max) 207 (4.36), 235sh (4.11), 312 (4.27); "max 3312, 2919, 2200, 1638 cm–1; #H
(CDCl3, 300 MHz) 9.31 (1H, bs, indol-1-yl-H), 7.90 (1H, d, J = 8 Hz, ArH), 7.42 (2H, m, ArH), 7.22 (1H,
t, J = 8 Hz, ArH), 4.63 (2H, s, indol-3-yl-CH2N), 3.20 (2H, q, J = 1.6 Hz, NCH2C'C), 3.13 (2H, t, J = 8
Hz, NCH2CH2), 2.68 (2H, t, J = 8 Hz, CH2C=O), 2.20 (2H, quint, J = 8 Hz, NCH2CH2CH2), 1.90 (3H, t, J
= 1.6 Hz, CH3); m/z (CI) 267 (MH+, 100%); C17H18N2O requires 266.1419. Found 266.1414.
2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-7-phenylsulfonyl-6H-azocino[4,3-b]indol-6-one 28. To a stirred
solution of 2-(but-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-azocino[4,3-b]indol-6-one 27 (0.155 g, 0.58 mmol)
in dry DMF (10 mL), were added NaH (60% dispersion in mineral oil, 26 mg, 0.6 mmol) then, after H2
evolution ceased, PhSO2Cl (0.081 mL, 0.6 mmol) dropwise. After 1 h the mixture was poured into water
(50 mL) and poduct extracted into CH2Cl2. The dried extract was evaporated giving a brown oil which
was purified by chromatography (toluene:EtOAc, 99:1) to give the sulfonamido-ketone 28 as a white
crystalline solid (78 mg, 33%), mp 149-151 °C, $max (log %max) 206 (4.80), 246sh (4.37), 293sh (4.02); "max
2920, 2210, 1691 cm–1; #H (CDCl3, 300 MHz) 8.15 (2H, d, J = 7.5 Hz, ArH), 8.02 (1H, d, J = 7.5 Hz,
indol-7-yl-H), 7.60-7.30 (6H, m, ArH), 3.87 (2H, s, indol-3-ylCH2N), 3.40 (2H, s, NCH2C'C), 2.84 (4H,
m, NCH2CH2CH2), 2.02 (2H, m, NCH2CH2CH2), 1.83 (3H, t, J = 1.5 Hz, CH3); m/z (CI) 407 (MH+,
100%), 267 (90); C23H23N2O3S requires 407.1429. Found 407.1423.
5-(N-(E-But-2-en-1-yl)phenylsulfonylamido)-2-methyl-2-(1-phenylsulfonylindol-2-yl)pentan-2-ol 29.
To a stirred solution of 4-(N-(E-but-2-en-1-yl)phenylsulfonylamido)-1-(1-phenylsulfonylindol-2-yl)-
butan-1-one 19 (0.5 g, 0.9 mmol) in dry THF (50 mL) at rt was added MeMgCl (3 M solution in THF,
0.37 mL, 1.1 mmol) dropwise. The reaction mixture was heated at refluxed for 1 h, allowed to cool, then
poured into water (100 mL). The aqueous phase was extracted with Et2O (3 x 30 mL) and the combined
organic extracts dried. Concentration gave a yellow oil which was purified by chromatography
(toluene:EtOAc, 9:1) to give the alcohol 29 as a colourless oil (0.48 g, 93%), $max (log %max) 207 (4.51),
242sh (4.20), 291sh (3.60); "max 3530, 2939 cm–1; #H (CDCl3, 300 MHz) 8.04 (1H, d, J = 7.5 Hz,

HETEROCYCLES, Vol. 82, No. 1, 2010
365
indol-7-yl-H), 7.83 (4H, m, ArH), 7.62-7.16 (9H, m, ArH), 6.70 (1H, s, indol-3-yl-H), 5.50 (1H, m,
HC=C), 5.20 (1H, m, C=CH), 4.95 (1H, bs, OH), 3.74 (2H, d, J = 7.5 Hz, NCH2C=C), 3.18 (2H, m,
NCH2CH2), 2.13 (2H, t, J = 7.5 Hz, CH2CHOH), 1.77 (3H, s, CH3), 1.60 (5H, d+m, C=CCH3 plus
CH2CH2CH2); m/z (CI) 552 (M+, 30%), 535 (74), 395 (92), 160 (100); C29H32N2O5S2 + NH4 requires
570.2096. Found 570.2110.
5-(E-But-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 30. A mixture of 5-(N-[E-but-2-en-1-yl]-
phenylsulfonylamido)-2-methyl-2-(1-phenylsulfonylindol-2-yl)pentan-2-ol 29 (0.42 g, 0.8 mmol),
Na2HPO4 (0.433 g, 3 mmol) and 6% sodium amalgam (10 g) were stirred together in dry MeOH (50 mL)
at rt. Decantation and evaporation followed by chromatography gave the alcohol 30 as a white crystalline
solid (0.158 g, 75%), mp 78-80 °C), $max (log %max) 226 (4.61), 274 (4.68); "max 3285, 3056, 2922, 2853
cm–1; #H (CDCl3, 300 MHz) 8.95 (1H, bs, indol-1-yl-H), 7.60 (1H, d, J = 7.5 Hz, ArH), 7.49 (1H, d, J =
7.5 Hz, ArH), 7.14 (2H, m, ArH), 6.20 (1H, s, indol-3-yl-H), 5.60 (2H, m, HC=CH), 4.79 (2H, bs, OH
plus NH), 3.17 (2H, d, J = 7 Hz, NCH2C=C), 2.75 (1H, m, one of NCH2CH2), 2.63 (1H, m, one of
NCH2CH2), 2.34 (1H, m, one of NCH2CH2CH2), 2.00 (1H, m, one of NCH2CH2CH2), 1.75 (5H, d+m,
C=CCH3 plus two of NCH2CH2CH2), 1.63 (3H, s, CCH3); m/z (CI) 273 (MH+, 26%), 255 (100);
C17H24N2O requires 272.1889. Found 272.1900.
2-(E-But-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 31. 5-(E-But-2-en-1-
ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 30 (0.117 g, 0.43 mmol), formalin (1.25 mL, 40%) and
AcOH (1.25 mL) in 1,2-dimethoxyethane (100 mL) were stirred togegher at rt for 0.5 h. Concetration and
extraction of product into Et2O (2 x 20 mL) produced brown oil which was purified by chromatography
(toluene:EtOH, 85:15). This gave the azocino-indole 31 as a white crystalline solid (0.122 g, 100%), mp
56-58 °C, $max (log %max) 230 (4.54), 284 (4.12); "max 3430, 3263, 2916, 2813 cm–1; #H (CDCl3, 300 MHz)
9.60 (1H, bs, indol-1-yl-H), 7.45 (1H, d, J = 7.5 Hz, ArH), 7.37 (1H, d, J = 7.5 Hz, ArH), 7.20 (1H, t, J =
7.5 Hz, ArH), 7.14 (1H, t, J = 7.5 Hz, ArH), 5.19 (2H, m, HC=CH), 4.26 (1H, d, J = 15 Hz, one of
indol-3-ylCH2N), 3.68 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.39 (1H, m, one of NCH2C=C), 3.25
(1H, m, one of NCH2C=C), 3.00 (1H, t, J = 9 Hz, one of NCH2CH2), 2.58 (1H, t, J = 9 Hz, one of
NCH2CH2), 2.02 (1H, t, J = 9 Hz, one of NCH2CH2CH2), 1.83 (3H, s, CCH3), 1.75 (3H, d, J = 7 Hz,
C=CCH3), 1.84-1.63 (3H, m, one of NCH2CH2CH2 plus NCH2CH2CH2); m/z (CI) 285 (MH+, 100%), 267
(18); C18H24N2O requires 284.1889. Found 284.1888.
5-((N-But-2-ynyl)phenylsulfonylamido)-2-methyl-2-(1-phenylsulfonylindol-2-yl)pentan-2-ol 32. To a
stirred solution of 4-((N-but-2-ynyl)phenylsulfonylamino)-1-(1-phenylsulfonylindol-2-yl)butan-1-one 21

366
HETEROCYCLES, Vol. 82, No. 1, 2010
(5.77 g, 10.8 mmol) in dry tetrahydrofuran (200 mL) at rt was added methylmagnesium chloride (3 M
solution in THF, 4.7 mL, 14.0 mmol) dropwise then the mixture was heated at reflux for 3 h. The reaction
mixture was allowed to cool, then poured into water (500 mL). The aqueous phase was extracted with
Et2O (3 x 300 mL) and the combined organic extracts dried. Evaporation and chromatography
(toluene:EtOAc, 9:1) gave the alcohol 32 as an orange oil (4.53 g, 76%), $max (log %max) 232 (4.55), 258
(4.68); "max 3531, 3300, 2939, 2280 cm–1; #H (CDCl3, 300 MHz) 8.04 (1H, d, J = 7.5 Hz, indol-7-yl-H),
7.87 (4H, m, ArH), 7.61-7.20 (9H, m, ArH), 6.74 (1H, s, indol-3-yl-H), 4.99 (1H, s, OH), 4.08 (2H, s,
NCH2C'C), 3.25 (2H, t, J = 7.5 Hz, NCH2CH2), 2.21 (2H, m, CH2C(Me)(OH)), 1.78 (3H, s, CH3), 1.55
(5H, s+m, CH2C'C, CH2CH2CH2); #C (CDCl3, 75 MHz) 147.5 (s), 139.0 (s), 138.1 (s), 137.8 (s), 133.8
(d), 132.5 (d), 129.1 (d), 129.0 (s), 128.7 (d), 127.8 (d), 127.0 (d), 126.6 (d), 125.2 (d), 124.3 (d), 121.2
(d), 115.6 (d), 112.6 (d), 81.8 (s), 71.6 (s), 71.5 (s), 46.5 (t), 39.5 (t), 36.9 (t), 28.0 (q), 22.7 (t), 3.1 (q);
m/z (CI) 550 (M+, 23%), 533 (100%), 411 (30), 393 (60), 227 (43), 160 (50), 78 (42); C29H30N2O5S2 +
NH4 requires 568.1940. Found 568.1946.
5-(But-2-ynylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 33. A suspension of Mg (10.0 g, 0.42 mol)
and NH4Cl (0.19 mol) in dry MeOH (500 mL) containing 5-((N-but-2-ynyl)phenylsulfonylamino)-
2-methyl-2-(1-phenylsulfonylindol-2-yl)butan-2-ol 32 (4.5 g, 8.0 mmol) was vigorously stirred for 2 h
(Caution – exothermic), then water (100 mL) added and the reaction mixture concentrated in vacuo. The
residue was dissolved in CH2Cl2 (100 mL), washed with water (50 mL) and dried. Filtration and
concentration gave a brown oil which was purified by chromatography (toluene:EtOAc:EtOH, 2:2:1) to
give the amine 33 as an orange oil (1.14 g, 52%), $max (log %max) 222 (4.66), 271 (4.33), 279 (4.31), 286
(4.20); "max 3410, 3292, 2920 cm–1; #H (CDCl3, 300 MHz) 8.84 (1H, bs, indol-1-yl-H), 7.58 (1H, d, J = 7.5
Hz, ArH), 7.40 (1H, d, J = 7.5 Hz, ArH), 7.16 (1H, t, J = 7.5 Hz, ArH), 7.12 (1H, t, J = 7.5 Hz, ArH),
6.28 (1H, s, indol-3-yl-H), 3.55 (2H, bs, OH and NH), 3.32 (2H, s, NCH2C'C), 2.88 (1H, m, one of
NCH2CH2), 2.51 (1H, m, one of NCH2CH2), 2.32 (1H, m, one of NCH2CH2CH2), 2.00 (1H, m, one of
NCH2CH2CH2), 1.85 (3H, s, CH3), 1.73 (2H, m, one of NCH2CH2CH2), 1.60 (3H, s, CH3); #C (CDCl3, 75
MHz) 146.6 (s), 134.9 (s), 129.3 (s), 120.8 (d), 120.0 (d), 119.5 (d), 110.9 (d), 96.3 (d), 79.9 (s), 75.9 (s),
70.6 (s), 48.4 (t), 42.9 (t), 37.6 (t), 31.9 (q), 24.4 (t), 3.5 (q); m/z (CI) 271 (MH+, 23%), 253 (100), 239
(25); C17H23N2O requires 271.1810. Found 271.1810.
2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 34. To a stirred solution of
5-(but-2-ynylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 33 (0.25 g, 0.9 mmol) in 1,2-dimethoxyethane
(250 mL), formalin (3 mL, 40%) and AcOH (3 mL) were added at rt. The solution was concentrated in
vacuo to ca. 5 mL and aqueous sodium hydroxide (10 mL) and Et2O (20 mL) were added. The layers

HETEROCYCLES, Vol. 82, No. 1, 2010
367
were separated, the aqueous phase re-extracted (Et2O, 2 x 20 mL) and the combined organic extracts dried.
Evaporation after filtration gave a brown oil which was purified by chromatography (toluene:EtOH,
85:15). This gave the azocino-indole 34 as a white crystalline solid (0.23 g, 88%) mp 178-180 °C, $max
(log %max) 230 (4.22), 284 (4.07), 292 (4.02); "max 3440, 3266, 2918 cm–1; #H (CDCl3, 300 MHz) 9.03 (1H,
bs, indol-1-yl-H), 7.46 (1H, d, J = 7.5 Hz, ArH), 7.34 (1H, d, J = 7.5 Hz, ArH), 7.15 (2H, m, ArH), 4.20
(1H, d, J = 15 Hz, one of indol-3-yl-CH2N), 3.89 (1H, d, J 15 Hz, one of indol-3-yl-CH2N), 3.57 (1H, q, J
= 1.6 Hz, one of NCH2C'C), 3.52 (1H, q, J = 1.6 Hz, one of NCH2C'C), 2.80 (2H, m, NCH2CH2),
2.02-1.63 (4H, m, NCH2CH2CH2), 1.86 (3H, t, J = 1.6 Hz, C'CCH3), 1.74 (3H, s, CH3); #C (CDCl3, 75
MHz) 138.6 (s), 134.0 (s), 127.4 (s), 125.6 (d), 121.6 (d), 119.4 (d), 118.0 (d), 110.7 (s), 81.7 (s), 73.1 (s),
69.3 (s), 55.1 (t), 50.9 (t), 48.0 (t), 43.0 (t), 27.6 (q), 24.7 (t), 3.6 (q); m/z (CI) 282 (M+, 20%), 265 (38),
249 (34), 229 (38), 182 (40), 173 (100), 152 (67); C18H22N2O requires 282.1732. Found 282.1730.
5-(2-Tri-n-butylstannyl-(Z)-but-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 35. A solution of
5-(but-2-ynylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 33 (0.613 g, 2.3 mmol), n-Bu3SnH (6 mL, 7.7
mmol) and AIBN (0.1 g) in PhH (20 mL) was heated at reflux for 30 h. Concentration gave a yellow
liquid which was filtered through a short column of silica to remove excess n-Bu3SnH. The silica was
extracted with MeOH and concentration of the extract gave a brown oil which was purified by
chromatography (EtOAc) to give the stannane 35 as an orange oil (0.53 g, 42%), $max (log %max) 228 (4.28),
274 (4.05), 280 (4.06), 288 (3.96); "max 3301, 2956, 2925, 2853 cm–1; #H (CDCl3, 300 MHz) 8.66 (1H, bs,
indol-1-yl-H), 7.55 (1H, d, J=7.5 Hz, ArH), 7.32 (1H, d, J=7.5 Hz, ArH), 7.10 (2H, m, ArH), 6.20 (2H,
s+m, indol-3-yl-H plus C=CH), 3.21 (2H, s, NCH2C=C), 2.67 (1H, m, one of NCH2CH2), 2.52 (1H, m,
one of NCH2CH2), 2.26 (1H, m, one of NCH2CH2CH2), 1.96 (1H, m, one of NCH2CH2CH2), 1.75 (5H,
d+m, J=7 Hz, C=CCH3 plus two of NCH2CH2CH2), 1.70-1.20 (18H, m, Sn(CH2CH2CH2)3, 1.55 (3H, s,
CCH3), 0.90 (9H, t, J=10 Hz, 3xCH2CH3); m/z (EI) 563 (MH+, 4%), 545 (5), 487 (100), 368 (20), 350 (20),
182 (49); (MM 487.2142. C29H50N2OSn – H2O – C4H9 requires 487.2135).
5-(Z-2-Iodobut-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 36a and 5-(Z-2-Iodobut-2-en-1-
ylamino)-2-methyl-2-(3-iodoindol-2-yl)pentan-2-ol 36b. Method (a). To a stirred solution of
5-(2-tri-n-butylstannyl-(Z)-but-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 35 (0.1 g, 0.21 mmol)
in CH2Cl2 (5 mL) at rt was added I2 (52 mg, 0.21 mmol). The solution was stirred for 15 min then
decolourised by washing with 1N aq Na2S2O3 solution and dried. Concentration gave a purple oil which
was purified by chromatography using (toluene:EtOH, 9:1) to give the iodide 36a as a colourless oil (14
mg, 17%), $max (log %max) 228 (4.36), 276 (4.28), 288 (4.17); "max 3420, 3286, 2922, 2852 cm–1; #H (CDCl3,
300 MHz) 8.70 (1H, bs, indol-1-yl-H), 7.56 (1H, d, J = 7.5 Hz, ArH), 7.38 (1H, d, J = 7.5 Hz, ArH), 7.12

368
HETEROCYCLES, Vol. 82, No. 1, 2010
(2H, m, ArH), 6.19 (1H, s, indol-3-yl-H), 5.75 (2H, q, J = 7 Hz, C=CH), 3.36 (2H, s, NCH2C=C), 2.73
(2H, bs, OH, NH), 2.63 (1H, m, one of NCH2CH2), 2.45 (1H, m, one of NCH2CH2), 2.32 (1H, m, one of
NCH2CH2CH2), 1.96 (1H, m, one of NCH2CH2CH2), 1.75 (3H, d, J = 7 Hz, C=CCH3), 1.73-1.52 (2H, m,
two of NCH2CH2CH2), 1.57 (3H, s, CCH3); m/z (EI) 398 (M+, 8%), 380 (22), 365 (80), 280 (30), 253 (75),
210 (50), 184 (55), 157 (100); C17H23IN2O requires 398.0855. Found 398.0862.
Method (b). In a similar manner, 5-(2-tri-n-butylstannyl-(Z)-but-2-en-1-ylamino)-2-methyl-2-(indol-2-
yl)pentan-2-ol 35 (0.53 g, 1.09 mmol) in CH2Cl2 (10 mL) and I2 (1.38 g, 5.5 mmol) gave a purple oil from
which product was obtained by chromatography (toluene:EtOH, 9:1) to give firstly diiodide 36b as a
colourless oil (0.2 g, 35%), $max (log %max) 230 (4.70), 278 (4.89); "max 3410, 3286, 2922, 2850 cm–1; #H
(CDCl3, 300 MHz) 9.38 (1H, bs, indol-1-yl-H), 7.39 (2H, m, ArH), 7.18 (2H, t, J = 7.5 Hz, ArH), 5.81
(2H, q, J = 7 Hz, C=CH), 3.40 (2H, s, NCH2C=C), 3.33 (1H, m, one of NCH2CH2), 3.27 (2H, bs, OH,
NH), 3.02 (1H, m, one of NCH2CH2), 2.66 (1H, m, one of NCH2CH2CH2), 1.86 (1H, m, one of
NCH2CH2CH2), 1.76 (3H, d, J = 7 Hz, C=CCH3), 1.70 (2H, m, one of NCH2CH2CH2), 1.62 (3H, s,
CCH3); m/z (EI) 525 (M+, 50%), 399 (37), 381 (62), 316 (42), 253 (38), 160 (40). Next from the column
was iodide 36a as a colourless oil (0.1 g, 23%). All spectra were as above.
2-(2-Tri-n-butylstannyl-(Z)-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-
ol 38. 2-(But-2-ynyl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 34 (230 mg, 0.82
mmol) was dissolved in PhH and the solution degassed under nitrogen. Azobisisobutyronitrile (50 mg,
0.30 mmol) and tri-n-butyltin hydride (2 mL, 7.4 mmol) were added and the mixture heated at reflux for 3
h. Most of the solvent was removed in vacuo and the resulting solution filtered through a short pad of
silica, eluting first with petroleum ether:Et3N, 99:1, to remove excess tin hydride, and then with
petroleum ether:EtOAc:Et3N, 49.5:49.5:1 to give the stannane 38 as a yellow oil (310 mg, 65%), $max (log
%max) 228 (4.56), 284 (3.89); "max 3272, 2954, 2924, 1460, 740 cm–1; #H (CDCl3, 300 MHz) 9.15 (1H, bs,
indol-1-yl-H), 8.40 (1H, bs, OH), 7.50 (1H, m, ArH), 7.31 (1H, m, ArH), 7.17 (1H, m, ArH), 6.49 (1H, q,
J = 6.4 Hz, C=CH), 4.37 (1H, d, J = 15.8 Hz, one of indol-3-ylCH2N), 3.63 (1H, d, J = 15.8 Hz, one of
indol-3-ylCH2N), 3.49 (1H, d, J=14.2 Hz, one of NCH2C=C), 3.32 (1H, d, J = 14.2 Hz, one of NCH2C=C),
3.00 (1H, m, one of NCH2CH2), 2.55 (1H, m, one of NCH2CH2), 2.07 (1H, m, one of NCH2CH2CH2),
1.95-1.35 (27H, m, 3xSnCH2CH2CH2 plus one of NCH2CH2CH2 plus C=CCH3 plus CCH3 plus
CH2CH2CH2), 0.98 (9H, t, J = 7.2 Hz, 3xCH2CH3); #C (CDCl3, 75 MHz) 139.2 (s), 138.2 (d), 134.1 (s),
127.7 (s), 122.5 (s), 121.4 (d), 119.2 (d), 117.9 (d), 111.0 (d), 110.6 (s), 69.3 (s), 66.5 (t), 57.1 (t), 50.8 (t),
43.1 (t), 29.3 (t), 27.7 (q), 27.5 (t), 24.6 (t), 20.3 (q), 13.8 (q), 10.3 (t); m/z (CI) 575 (MH+, 100%), 557
(62), 517 (10), 499 (20); C26H41N2O120Sn (i.e. M-C4H9) requires 517.2240. Found 517.2223.

HETEROCYCLES, Vol. 82, No. 1, 2010
369
2-(2-Iodo-(Z)-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 37. Method
(a): 5-(2-Iodo-Z-but-2-en-1-ylamino)-2-methyl-2-(indol-2-yl)pentan-2-ol 36a (0.1 g, 0.25 mmol),
formalin (1 mL, 40%) and AcOH (1 mL) in 1,2-dimethoxyethane (100 mL) were stirred together for 30
min. Concentration in vacuo to ca. 5 mL, addition of aq NaOH (10 mL) and Et2O (20 mL), separation of
the layers, re-extraction of the aq layer, and finally drying of the organic solution and evaporation
produced a brown oil which was purified by chromatography (toluene:EtOH, 85:15). This gave the
azocino-indole 37 as a colourless oil (0.085 g, 83%), $max (log %max) 228 (4.77), 278 (4.87); "max 3420,
3264, 2917 cm–1; #H (CDCl3, 300 MHz) 9.62 (1H, bs, indol-1-yl-H), 7.41 (1H, d, J = 7.5 Hz, ArH), 7.35
(1H, d, J = 7.5 Hz, ArH), 7.19 (1H, t, J = 7.5 Hz, ArH), 7.14 (1H, t, J = 7.5 Hz, ArH), 5.94 (1H, q, J = 7
Hz, C=CH), 4.22 (1H, d, J = 15 Hz, one of indol-3-ylCH2N), 3.76 (1H, d, J = 15 Hz, one of
indol-3-ylCH2N), 3.12 (2H, s, NCH2C=C), 2.95 (1H, t, J = 9 Hz, one of NCH2CH2), 2.52 (1H, t, J = 9 Hz,
one of NCH2CH2), 2.05 (1H, t, J = 9 Hz, one of NCH2CH2CH2), 1.80 (3H, s, CCH3), 1.75 (3H, d, J = 7 Hz,
C=CCH3), 1.84-1.65 (3H, m, three of NCH2CH2CH2); #C (CDCl3, 125 MHz) 138.7 (s), 134.8 (d), 133.8
(s), 127.4 (s), 121.6 (d), 119.3 (d), 117.7 (d), 110.9 (d), 110.3 (s), 104.5 (s), 71.9 (t), 69.2 (s), 56.7 (t),
50.9 (t), 42.9 (t), 27.6 (q), 24.6 (t), 22.1 (q); m/z (CI) 411 (MH+, 100%), 393 (42), 316 (23), 269 (28), 211
(36); C18H23IN2O requires 410.0857. Found 410.0856.
Method (b): To a solution of 2-(2-tri-n-butylstannyl-(Z)-but-2-en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-
methylazocino[4,3-b]indol-6-ol 38 (285 mg, 0.5 mmol) in CH2Cl2 (1 mL) was added I2 (632 mg, 2.50
mmol) and the resulting mixture stirred at rt for 35 min, quenched with aq Na2S2O3 and product extracted
into CH2Cl2. Evaporation gave crude material which was purified by chromatography over silica
(toluene:EtOAc, 95:5!9:1). Further partitioning between petroleum ether and MeCN gave highly pure
product 37 (74 mg, 36%).
2-(2-Iodo-Z-but-2-en-1-yl)-1,2,3,4,-tetrahydro-6-methylazocino[4,3-b]indole 3. 2-(2-Iodo-(Z)-but-2-
en-1-yl)-1,2,3,4,5,7-hexahydro-6H-6-methylazocino[4,3-b]indol-6-ol 37 (80 mg, 0.20 mmol) was
dissolved in PhH with heating to 50 °C. p-toluenesulfonic acid (10 mg, 0.05 mmol) was added and the
mixture heated at 50 °C for 30 min. The solvent was evaporated in vacuo and the residue partitioned
between aq NaHCO3 and CH2Cl2. The organic extract was dried and evaporated to give the alkene 3 as an
oil (52 mg, 66%), $max (log %max) 234 (4.34), 296 (4.11); "max 3408, 2927, 2913, 1644 cm–1; #H (CDCl3, 300
MHz) 8.04 (1H, bs, indol-1-yl-H), 7.59 (1H, d, J = 7.5 Hz, ArH), 7.34 (1H, d, J = 7.5 Hz, ArH), 7.14 (2H,
t, J = 7.5 Hz, ArH), 5.84 (2H, m, 2xC=CH), 4.00 (2H, s, indol-3-ylCH2N), 3.37 (2H, s, NCH2C=C), 2.72
(2H, m, NCH2CH2), 2.18 (5H, s+m, NCH2CH2 plus CCH3), 1.80 (3H, d, J = 7 Hz, C=CCH3); m/z (EI) 392
(M+, 19%), 183 (55), 168 (60), 133 (41); C18H21IN2 requires 392.0751. Found 392.0766.

370
HETEROCYCLES, Vol. 82, No. 1, 2010
ACKNOWLEDGEMENTS
JGK thanks the SERC and EPSRC for maintenance grants and DR similarly acknowledges his University
of Manchester Gratrix scholarship.
REFERENCES
1. J. A. Joule, H. Monteiro, L. J. Durham, B. Gilbert, and C. Djerassi, J. Chem. Soc., 1965, 4773.
2. J. A. Joule, The Chemistry of Heterocyclic Compounds, Vol 25, Indoles, Part 4, 265-292, Ed. by J. E.
Saxton, Wiley-Interscience, New York, 1983; M. Alvarez and J. A. Joule, The Chemistry of
Heterocyclic Compounds, Vol 25, Indoles, Supplement to Part 4, 261-278, Ed. by J. E. Saxton,
Wiley-Interscience, New York, 1994.
3. D. I. C. Scopes, M. S. Allen, G. J. Hignett, N. D. V. Wilson, M. Harris, and J. A. Joule, J. Chem.
Soc., 1977, 2376.
4. M.-L. Bennasar, E. Zulaica, D. Solé, T. Roca, D. García-Díaz, and S. Alonso, J. Org. Chem., 2009,
74, 8359.
5. J. D. Street, M. Harris, D. I. Bishop, F. Heatley, R. L. Beddoes, O. S. Mills, and J. A. Joule, J. Chem.
Soc., Perkin Trans. 1, 1987, 1599.
6. R. J. Sundberg and H. F. Russell, J. Org. Chem., 1973, 38, 3324.
7. J. A. Joule, M. S. Allen, D. I. Bishop, M. Harris, G. J. Hignett, D. I. C. Scopes, and N. D. V. Wilson,
Indole and biogenetically related alkaloids, Ed. by J. D. Phillipson and M. H. Zenk, Academic Press,
London, 1980, 2376.
8. A. R. Katritzky and K. Akutagawa, Tetrahedron Lett., 1985, 26, 5935.
9. K. Okabe and M. Natsume, Tetrahedron, 1991, 47, 7615.
10. H. E. Ensley, R. R. Buescher, and K. Lee, J. Org. Chem., 1982, 47, 404.
11. E. Negishi, Y. Zhang, and V. Bagheri, Tetrahedron Lett., 1987, 28, 5793; S. Sharma and A. C.
Oehlschlager, J. Org. Chem., 1989, 54, 5064.