A novel synthesis of (±)-harmacine and (±)1,2,3,4,6,7,12,12b- octahydroindole[2,3-a]quinolizine

Article abstract of DOI:10.1002/jhet.5570440634

(Chemical Equation Presented) A three-step synthesis of (±)-harmacine is described from the readily available 4,4-diethoxybutan-1-amine via an acid-mediated acyl iminium ion cyclisation. The synthesis of the homologous (±)1,2,3,4,6,7,12,12b-octahydroindole[2,3-a] quinolizine from 5,5-diethoxypentan-1-amine is also described. Although similar, the two systems required very different cyclisation conditions.

Full text of DOI:10.1002/jhet.5570440634

Nov-Dec 2007
1459
A Novel Synthesis of (±)-Harmacine and (±)1,2,3,4,6,7,12,12b-
Octahydroindole[2,3-a]quinolizine
Frank D. King
Dept. of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K
Received March 25, 2007
O
O
NH(CH2)nCH(OEt)2
N
N
(CH2)n
(CH2)n
N
N
N
H
H
n = 1 or 2
H
A three-step synthesis of (±)-harmacine is described from the readily available 4,4-diethoxybutan-1-
amine via an acid-mediated acyl iminium ion cyclisation. The synthesis of the homologous
(±)1,2,3,4,6,7,12,12b-octahydroindole[2,3-a]quinolizine from 5,5-diethoxypentan-1-amine is also
described. Although similar, the two systems required very different cyclisation conditions.
J. Heterocyclic Chem., 44, 1459 (2007).
O
NHR
INTRODUCTION
N
H2NOC
We have had a long-standing interest in the pharma-
cology of conformationally restricted tryptamines, as
exemplified by the identification of PU 46905 1 [1] that
led to the discovery of the anti-migraine drug,
Frovatriptan 2 [2].
N
N
H
CHO
1 R = H
2 R = Me
9
As an alternative form of the ethylamine conforma-
tional restriction, the alkaloid harmacine 3 (Scheme I)
attracted our attention. Harmacine has been used as an
intermediate both for a number of indole alkaloids [3] and
to a series of dopamine/serotonin receptor ligands [4].
We were particularly interested in developing a library of
harmacine analogues for pharmacological evaluation. For
this we wanted a facile synthesis that gave the potential
for the introduction of additional functionality. The
proposed methodology via an acid-mediated acyliminium
ion cyclisation is shown in Scheme I. For library
synthesis, the intermediate lactams 5 and 6 are
attractive in that they contain two sites for substitution,
the indole N and the indole acetate CH2. Additional
functionality can be included by using substituted
indole acetic acids or by using our previously published
substituted 4,4-diethoxybutan-1-amines and 5,5-dieth-
oxypentan-1-amines [5].
Literature precedent for the proposed cyclisations to 5
and 6 was not encouraging. The reported attempted
cyclisation of 8 in formic acid gave none of the desired
lactam 6, but gave a spiro product 9, believed to be
produced by spiro-cyclisation to the indolenine followed
by reduction and formylation [6]. However, cyclisations
under non-reducing conditions had not been investigated
and therefore this reaction warranted further investigation.
The synthesis of the lactam 6 in 11 steps from quinoline
has been reported, but with little exploration of its
chemistry [7].
RESULTS AND DISCUSSION
Compounds 7 and 8 were prepared from indole-3-
acetic acid and 4-aminobutyraldehyde diethylacetal and
5-aminovaleraldehyde diethylacetal [6,8,9] (95%
yield), respectively, via the N-hydroxysuccinimide
active ester.
Scheme I
O
O
O
NHCH2(CH2)nCH2CH(OEt)2
+
N
N
N
(CH2)n
(CH2)n
(CH2)n
N
N
H
N
H
N
H
H
3 n = 1
4 n = 2
5 n = 1
6 n = 2
7 n = 1
8 n = 2

1460
F. D. King
Vol 44
For the cyclisation of 7 to 5, various acids in CH2Cl2
distinctive two singlets at ꢀ 9.26 and 9.17 in a ratio of
1:1.4, assigned as the protonated imine C-H protons of
each diastereomer of 10. The 13C NMR spectrum in TFA
was also simplified, showing 29 signals, most of which
were closely paired signals with again a ~1:1.4 ratio,
corresponding to diastereomeric mixture of the TFA salt
of 10.
solution at ambient temperatures were investigated,
including TFA (4 equivs., 1 h 43% yield), ethereal HCl
(15 equivs, 1 h, 8% yield), AlCl3 (0.5 equiv., 4 h, 55%
yield; 1 equiv., 30 min, 41% yield; 1 equiv., 3 h, 71%
yield; 2 equiv. 30 min, 62% yield), TiCl4 (1 equiv., 4 h,
42% yield) and BF3.OEt2 (1 equiv., 2 h, 91% yield). The
yields quoted are based upon an LC/MS analysis of the
reaction mixtures quenched with MeOH. From these trial
reactions, BF3.OEt2 appeared to be the best.
The synthesis was repeated on a preparative scale (0.01
M) using BF3.Et2O (1 equiv.) to give 5 in a yield of 92%.
The reduction of 5 to give the desired (±)-harmicine 3 was
effected with either AlH3 (from LAH and H2SO4 in THF)
(81% yield) or BH3 followed by acid hydrolysis (87%
yield). Thus, the 5-membered iminium ion cyclisation
gave the desired (±)-harmicine in 3 steps in an overall
yield of 69%.
N
N
O
O
N
O
N
N
N
N
N
11
10
O
If the isolated solid were the trimer 11, it would have
nine stereogenic centres and would probably exist as a
multitude of isomers, which could explain the complex
nature of the NMR spectrum of the isolated solid. In
addition, the previously reported trimer of 3,3-dimethyl-
indolenine exists as approximately 15% of the indolenine
in neutral solution at room temperature, presumably in
equilibrium with the trimer [10]. In fact, in the DMSO
spectrum of the putative solid 11, two small imine CH
peaks can be seen at ꢀ 8.35 and ꢀ 8.27, the comparative
integration with the total aromatics suggesting 15% of 10
being present. This complex nature of 11 could also
explain the failed attempts at purification and
crystallization. Thus although there is no direct evidence
of the solid to be the trimer 11, the spectroscopic
properties are consistent with the proposed structure.
In the reported formic acid cyclisation of 8 to 9, the
authors proposed that 10 was an intermediate, though no
evidence was presented [6]. In order to investigate this,
the putative trimer 11 was heated under reflux in formic
acid, under which conditions 11 would be expected to
revert to the monomer 10, and then to be reduced and
formylated. LC/MS indicated the formation of a new
mixture of products consistent with the formation of the
Following the above success, the cyclisation was
attempted on 8. The formic-acid mediated cyclisation
was reported to give the spiro product 9 as a mixture of
diastereomers [6]. Although the diastereomers were
separated, no definitive assignment of stereochemistry
was made. It was hoped that alternative, non-reducing
conditions would result in the formation of alternative
products.
The acid-induced cyclisations investigated for 7 were
applied to 8, but there was no evidence of any 2,3-fused
product 6 being formed. In the majority of cases, LC/MS
indicated the formation of dimers and trimers of the
intermediated acyliminium ion. However, the use of
TMS-triflate (5 equiv., 70% yield by LC/MS), or better
TFA (6 equivs., 91% yield by LC/MS), gave a mixture of
products with a molecular weight from EI MS consistent
with the formation of a cyclic product. The TFA reaction
was repeated on a preparative scale (6mM) and, after
basification, a product was isolated as an off-white,
amorphous solid (92% theoretical yield).
Reverse phase analytical LC/MS suggested that the
solid was a mixture of at least two products in >98%
purity and the CI HRMS was consistent with the
formation of the 3,3-spiroindolenine 10. However, the 1H
NMR spectra in both CDCl3 and d6-DMSO were very
complex and no meaningful 13C NMR in CDCl3 could be
obtained. It was not possible to separate the products
preparatively on either SiO2 or Al2O3 using any of the
normal phase solvent systems investigated. However,
FAB MS of the product gave an MH+ peak at 721,
indicative that the indolenine 10 may have trimerised.
3,3-Dimethyl-indolenine has been reported to trimerise to
form a hexahydro-1,3,5-triazine, which exist mainly as
the triazine at room temperature in neutral solvents, but as
the monomeric indolenine either at elevated temperature
or in TFA [10,11]. Running the NMR of the isolated
formamide 9 as a mixture of diastereomers.
The
diastereomers were readily separable by normal phase
chromatography on a preparative scale to give the two
isomers as oils.
1
The H NMR of these isomers was consistent with the
NMR's reported for the two isomers 9a and 9b [6]. A key
difference between 9a and 9b is that the bridgehead 8a'
proton of the indolizidine sits very close to one of the
2-indoline protons for 9b, whereas for 9a it is very close to
the 4-indoline proton. From a more detailed NMR
analysis of the more polar isomer 9b, the bridgehead 8a'
proton was identified as the dd at ꢀ 3.41, coupled to both
protons on position 8'. From NOE experiments, irradiation
1
solid in TFA simplified the H NMR spectrum, giving a

Nov-Dec 2007
A Novel Synthesis of (±)-Harmacine
1461
of this 8a' proton showed a strong NOE with the 2-indoline
proton at ꢀ 4.24, together with the adjacent 8' equatorial
proton on the indolizidine ring plus a weaker interaction
with the axial 5' proton adjacent to the indolizidine N.
There was no NOE interaction with the 4-indoline proton.
Thus the more polar isomer 9b is conclusively assigned
the stereochemistry 3S,8a'R/ 3R,8a'S.
and 6-membered cyclic iminium ions. Acid treatment of
the acetal 7 gave directly the fused lactam 5 with no
intermediate spiro-lactam being identified. Therefore,
assuming the expected mechanism [11], if the spiro-
lactam did form, this must have rearranged immediately
to the fused product. In contrast, for acetal 8, it was found
that the spirolactam 10 was unexpectedly stable and
required very much more forcing conditions to effect the
rearrangement to the fused lactam 6.
O
O
5'
N
H
4
N
H
8a'
EXPERIMENTAL
2
N
8'
N
HCO
R
Melting points are uncorrected. NMR spectra were recorded
on a Bruker AM-400 spectrometer using Me4Si as internal
standard. All solvents and reagents were of commercial grade
and used without purification. All evaporations of solvents were
carried out under reduced pressure. All compounds and crude
reaction mixtures were analysed by LC/MS using an HP1050
LC system operating under reverse phase using a 3.3cm x
4.6mm ID, 3um ABZ+PLUS column with a 5 min. run, starting
with 0.1% formic acid + 10mM ammonium acetate and finishing
with acetonitrile + 0.05% formic acid, with a UV detection
range of 215 to 330nm. MS detection used a Waters ZQ mass
9a
9b R = CHO
12 R = H
In the original publication [6], the separated spiro-
indolines 9 were hydrolysed with picric acid. The less
polar isomer did not give a crystalline picrate, however
the more polar isomer did. In the text, it was stated that
the picrate of the indoline 12 had been formed. However,
in the experimental section, the calculated analytical data
was presented for the picrate salt of 10, and hence it was
registered as such in the ACS registry as number 61774-
69-4. The quoted CHN analysis data fitted equally well
for both the picrate salt of 10 and 12. In order to clarify
which product had been formed, the more polar isomer 9b
was hydrolysed with picric acid and as reported, a highly
crystalline picrate was obtained. Mass spectral (MH+ 243
daltons) and NMR analyses confirmed that the structure is
that of the picrate of the spiroindoline 12 and not that of
the spiroindolenine 10.
Assuming that the solid 11 is the hexahydro-triazine,
possible conditions for its conversion to the 2,3-fused
lactam 6 were investigated. It is well known that
3,3-dialkylindolenines can undergo acid-catalysed
rearrangements, often under very mild conditions, to the
2,3-disubstituted indoles [12]. However, in acidic media
at ambient temperatures, 11 was only converted into the
indolenine 10, which showed no evidence of rearranging.
However, under the much more forcing conditions of
heating with triflic acid at 100°C in dioxan for 1 h, a 58%
yield of 6 was obtained. Reduction of the lactam 6 using
alane, as described for 5, gave the required quinolizidine 4
in a 71% yield.
spectrometer and all products were 98% pure.
HRMS
measurements were performed with a Micromass Q-Tof 2
hybrid quadrupole time-of-flight mass spectrometer, equipped
with a Z-spray interface and the elemental composition was
calculated using MassLynx v4.0
Synthesis of N-(4,4-diethoxybutyl)-2-(3-indolyl)acetamide
(7). DCC (4.1 g, 0.02 mol.) was added in one portion to a stirred
solution of 3-indolylacetic acid (3.5 g, 0.02 mol.) and HOSu (2.3
g, 0.02 mol.) in EtOAc (150 mL) at ambient temperatures under
Argon. After stirring for 6 h., a solution of 4,4-diethoxybutan-1-
amine (ex. Aldrich, 90% pure) (3.4 mL, 0.02 mol.) in EtOAc (20
mL) was added in one portion. The reaction mixture was stirred
over night. Et2O (200 mL) was then added and the precipitated
DCU collected by filtration, and washed with Et2O (100 mL).
The combined filtrate was washed with 2 N NaOH (50 mL),
H2O (50 mL), brine (50 mL) and then dried (MgSO4), filtered
and concentrated by rotary evaporation to give (7) as a viscous
orange oil (6.4 g, 100%). LC/MS indicated 97% purity. 1H
NMR (400 MHz, CDCl3): ꢀ 1.15 (t, J = 7.2Hz, 6H), 1.40-1.60
(m, 4H), 3.17-3.22 (m, 2H), 3.34-3.40 (m, 2H), 3.50-3.57 (m,
2H), 3.73 (s, 2H), 4.37 (t, J = 5.2Hz, 1H), 5.80 (brs, 1H), 7.11-
7.16 (m, 2H), 7.23 (t, J = 8 Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 7.55
(d, J = 7.6 Hz, 1H), 8.50 (brs, 1H). 13C NMR and DEPT (75
MHz, CDCl3): ꢀ 15.3 (CH3), 15.3 (CH3), 24.6 (CH2), 30.8 (CH2),
33.5 (CH2), 39.2 (CH2), 61.2 (CH2), 102.5 (CH) 108.7 (C), 111.5
(CH), 118.6 (CH), 119.9 (CH), 122.5 (CH), 123.9 (CH), 127.0
(C), 136.5 (C), 171.7 (C). HRMS: calcd for C18H29NO5Na
[M+Na]+, 341.1841 found 341.1840.
Having converted the acetal 8 to the putative trimer 11,
and then to the lactam 6, the direct cyclisation of 8 to 6
was investigated. Heating 8 in dioxan with triflic acid
did, indeed, give the lactam 6 in a 47% isolated yield.
Thus alkaloid 4 was successfully prepared from 8 in a
three-step synthesis in an overall yield of 33%, or by a
four-step synthesis in an overall yield of 38%.
Synthesis of (±) 2,3,11,11b-tetrahydro-1H-indolizino[8,7-
b]indol-6-one (5). BF3.OEt2 (0.9 mL, 0.007 mol) was added to a
stirred solution of 7 (2.15 g, 0.007 mol) in CH2Cl2 (80 mL) at
ambient temperatures. After 2 h, H2O (5 mL) was added and
stirring was continued for 5 min. Et2O (100 mL) was added and
the solid collected, washed with H2O (10 mL) and Et2O (20 mL).
The organic layer from the filtrate was separated, dried (MgSO4)
and concentrated to give a solid. The two solid samples were
combined and purified by column chromatography (SiO2,
In conclusion, this work illustrates an interesting
difference between the intramolecular cyclisations of 5-

1462
F. D. King
Vol 44
CH2Cl2 to 10% MeOH/CH2Cl2). Trituration of the purified
product with Et2O gave 5 as a pale yellow solid (1.41 g, 92%)
m.p. 221-2° (dec.). 1H NMR (400 MHz, CDCl3): ꢀ 1.56-1.65
(m, 1H), 1.89-2.09 (m 2H), 2.50-2.56 (m, 1H), 3.36-3.71 (m,
4H), 4.70-4.7 (m, 1H), 6.98 (t, J = 8Hz, 1H), 7.09 (t, J = 8 Hz,
1H), 7.35 (d, J = 8 Hz, 1H), 7.43 (d, J = 8Hz, 1H), 11.20 (brs,
1H); 13C NMR and DEPT (75 MHz, d6-DMSO): ꢀ 22.1 (CH2),
29.9 (CH2), 31.9 (CH2), 44.2 (CH2), 55.9 (CH), 104.0 (C), 111.2
(CH), 118.0 (CH), 118.7 (CH), 121.2 (CH), 125.4 (C), 131.8
(C), 136.7 (C), 166.5 (C).
Hz, 0.6H), 3.00 (d, J = 18 Hz 0.4H), 3.13 (d, J = 18 Hz, 0.4H),
3.38 (dd, J = 1.6, 18 Hz 0.6H), 3.97 – 4.20 (m, 2H), 7.38 – 7.56
(m, 4H), 9.17 (s, 0.6H), 9.26 (s, 0.4H). 13C NMR and DEPT
(100 MHz, TFA): ꢀ 24.6 (CH2), 24.7 (CH2), 25.0 (CH2), 30.1
(CH2), 30.4 (CH2), 38.0 (CH2), 38.5 (CH2), 44.9 (CH2), 45.3
(CH2), 62.1 (C), 62.1 (CH), 62.7 (C), 67.6 (CH), 120.4 (CH),
120.7 (CH), 125.8 (CH), 127.4 (CH), 133.4 (CH), 133.5 (CH),
133.9 (CH), 134.7 (CH), 137.6 (C), 138.5 (C), 142.1 (C), 142.4
(C), 175.6 (C), 176.0 (C), 181.8 (CH), 182.3 (CH).
Synthesis of trans-(±)-1-formyl-1,2,6',7',8',8'a-hexa-hydro-
spiro[3H-indole-3,1'(5'H)-indolizin]-3'(2'H)-one (9a) and cis-
(±)-1-formyl-1,2,6',7',8',8'a-hexahydro-spiro[3H-indole-3,
1'(5'H)-indolizin]-3'(2'H)-one (9b). A solution of 11 (0.57 g,
0.00024 mol) in formic acid (20 mL), H2O (20 mL) and Na2CO3
(4 g) was heated under reflux for 1h. The cooled reaction
mixture was concentrated in vacuo to about half the volume,
carefully basified with solid K2CO3 and the product extracted
into CH2Cl2 (3 x 30 mL), dried (MgSO4) and concentrated. The
isomers were separated by column chromatography on SiO2,
starting with EtOAc with increasing quantities of MeOH to a
Synthesis of (±) Harmacine (3). a) with alane: cH2SO4 (0.08
mL, 0.0033 mol) was added, dropwise, over 5 min. to a stirred
solution of LAH (3.5 mL of a 1 M solution, 0.0035 mol) in dry
THF (10 mL) at 0°C under argon. After stirring at 0°C for 15
min, 5 (0.5 g, 0.0022 mol) was added in one portion and the
reaction heated under reflux for 1 h. The reaction mixture was
then cooled to 0°C and ice (0.5 g), then 2 N NaOH (3 mL) in
THF (20 mL) was then carefully added and the reaction mixture
stirred for 15 min. CH2Cl2 (100 mL) was then added and the
solid was collected and washed with CH2Cl2 (2 x 50 mL). The
combined organics were then evaporated in vacuo and the
residue purified by column chromatography (Al2O3, CH2Cl2) to
give the solid product (3) that was collected by trituration with
Et2O and dried (0.38 g, 81%) m.p. 174-5°C (lit. 173-4° [4]).
1
total of 2% to give. Fraction 1: (9a) as an oil (0.16 g, 25%) H
NMR (400 MHz, CDCl3): ꢀ 1.20-1.44 (m, 3H), 1.57-1.75 (m,
2H), 1.90-1.95 (m, 1H), 2.57 (dd, J = 5.6, 17Hz, 1H), 2.68 (brt, J
= 12.4, 1H), 2.82 (dq, J = 15.6, 1.6 Hz, 1H), 3.64-3.44 (m, 1H),
3.66 (dd, J = 0.8, 12.8, 0.8 H), 3.82 (d, J = 11.2, 0.2H), 4.12-4.19
(m, 1H), 4.40 (d, J = 10.8 Hz, 0.2H), 4.48 (d, J = 12.4 Hz, 0.8H),
7.11-7.33 (m, 3.8H), 8.07 (d, J = 8 Hz, 0.2H), 8.52 (s, 0.2H),
8.91 (s, 0.8H). HRMS: calcd. for C16H18N2O2 271.1447, found
271.1451. Fraction 2: (9b) as an oil (0.23g, 36%) 1H NMR (500
MHz, CDCl3): ꢀ 0.96 (q, J = 13 Hz, 1H), 1.24-1.38 (m, 3H),
1.71 (d, J = 13 Hz, 1H), 1.83 (d, J = 13 Hz, 1H), 2.57 – 2.72 (m,
2H), 2.79 (d, J = 17, 0.8H), 2.88 (d, J = 17Hz, 0.2H), 3.39 – 3.44
(m, 1H), 3.91 (d, J = 13 Hz, 0.8 H), 4.04 (d, J = 11 Hz, 0.2H),
4.15 – 4.26 (m, 2H), 7.09-7.33 (m, 3.8H), 8.09 (d, J = 8 Hz,
0.2H), 8.52 (s, 0.2H), 8.92 (s, 0.8H). HRMS: calcd. for
C16H18N2O2 271.1447, found 271.1448.
Synthesis of cis-(±)-1,2,6',7',8',8'a-hexahydro-spiro[3H-
indole-3,1'(5'H)-indolizin]-3'(2'H)-one (12). A solution of
(9b) (0.23 g, 0.00085 mol) and picric acid (60% + 40% H2O)
(0.32 g, 0.00085 mol) in isopropanol (20 mL) was heated under
gentle reflux for 1 h. On cooling, the picrate salt of (12)
deposited as orange crystals that were collected, washed with
Et2O (2 x 20 mL) and dried m pt. 209-210° (lit. 204.5-208.5°
[6]). 1H NMR (300 MHz, d6-DMSO): ꢀ 0.73-1.34 (m, 4H), 1.57
(brd, J = 13 Hz, 1H), 1.75 (brd, J = 13 Hz, 1H), 2.49 (s, 2H),
2.58-2.69 (m, 2H), 2.83 (d, J = 17 Hz, 1H), 3.52 (dd, J = 12, 3
Hz, 1H), 3.6 (d, J = 12 Hz, 1H), 3.95 (brd, J = 13 Hz, 1H), 7.20
– 7.48 (m, 4H), 8.58 (s, 2H); 13C NMR and DEPT (75 MHz, d6-
DMSO): ꢀ 23.0 (CH2), 23.8 (CH2), 27.0 (CH2), 40.2 (CH2), 41.4
(CH2), 48.8 (C), 57.0 (CH2), 63.9 (CH), 118.6 (CH), 125.2 (CH),
125.3 (CH), 127.6 (CH), 129.1 (CH), 136.2 (C), 139.1 (C),
141.8 (C), 160.7 (C), 170.7 (C). MS: MH+ 243.
1
LC/MS indicated 100% purity, MS 213.2 (MH+); H NMR (400
MHz, DMSO): ꢀ 1.78-1.84 (m, 3H), 2.14-2.22 (m 1H), 2.50-
2.56 (m, 1H), 2.67-2.72 (m, 1H), 2.76- 2.90 (m, 3H) 3.15-3.3.19
(m, 1H), 3.99-4.01 (m, 1H), 6.93 (t, J = 8Hz, 1H), 7.00 (t, J = 8
Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 7.35 (d, J = 8Hz, 1H), 10.76
(brs, 1H); 13C NMR and DEPT (75 MHz, CDCl3): ꢀ 17.9 (CH2),
23.5 (CH2), 29.5 (CH2), 46.0 (CH2), 49.4 (CH2), 57.0 (CH),
107.8 (C), 110.8 (CH), 118.1 (CH), 119.4 (CH), 121.4 (CH),
127.4 (C), 135.5 (C), 136.1 (C).
Synthesis of N-(5,5-diethoxypentyl)-2-(3-indolyl)acetamide
(8). Following the procedure described for (7), 5,5-diethoxy-
pentan-1-amine [8,9] (1.8 g, 0.01 mol) was converted to (8), (3.3
g, 100%) as an orange oil. 1H NMR (400 MHz, CDCl3): ꢀ 1.10-
1.30 (m, 8H including t, J = 7.2Hz), 1.30-1.42 (m, 2H) 1.50-60
(m, 2H), 3.17 (q, 2H, J = 6.8Hz), 3.40-3.51 (m, 2H), 3.55-3.63
(m, 2H), 3.73 (s, 2H), 4.38 (t, J = 5.2Hz, 1H), 5.73 (brs, 1H),
7.13-7.17 (m, 2H), 7.23 (t, J = 8 Hz, 1H), 7.41 (d, J = 8 Hz, 1H),
7.55 (d, J = 7.6 Hz, 1H), 8.52 (brs, 1H). 13C NMR and DEPT
(75 MHz, CDCl3): ꢀ 15.3 (CH3), 22.0 (CH2), 29.3 (CH2), 33.2
(CH2), 33.5 (CH2), 39.5 (CH2), 61.1 (CH2), 102.8 (CH) 108.8
(C), 111.5 (CH), 118.6 (CH), 119.9 (CH), 122.5 (CH), 123.9
(CH), 127.0 (C), 136.5 (C), 171.6 (C).
Synthesis of the putative trimer (11). A solution of (8) (2.0
g, 0.006 mol) and trifluoroacetic acid (3 ml, 0.04 mol) in CH2Cl2
(100 mL) was stirred at ambient temperatures for 1 h. The
reaction mixture was concentrated in vacuo and the residue
dissolved in Et2O (100 mL) and CH2Cl2 (50 mL), washed with 2
M NaOH (2 x 30 mL), H2O (30 mL) and brine (30 mL), and then
dried (MgSO4). Concentration of the filtered organic solution
gave an oil that solidified on stirring with Et2O (10 mL). The
solid was filtered and dried to give what is believed to be the
Synthesis of 1,2,3,4,12,12b-hexahydro-indolo[2,3-a]quino-
lizin-7-one (6). Method A: A solution of (11) (0.6 g, 0.0008
mol) and trifluoromethanesulfonic acid (0.22 mL, 0.0025 mol)
in dioxan (20 mL) was heated under reflux for 1 h. On cooling
to 0°C, the solvent was decanted and the residue triturated with
water. The solid was collected, dried and purified by column
chromatography (SiO2; CHCl3 + 2% MeOH) to give (6) as an
off-white solid (0.35 g, 58%). A small sample was recrystallised
from EtOH to give white crystals, m.p. 253-5° (lit. 254-255°
[7]). 1H NMR (400 MHz, CDCl3): ꢀ 1.30-1.40 (m, 2H), 1.62-
1
trimer (11) (1.4 g, 92%). CI MS (MH+) 721; H NMR (400
MHz, CDCl3): ꢀ 0.7 – 2.0 (m), 2.5-3.7 (m), 4.0–4.7 (series of
multiplets), 5.0–6.1 (series of multiplets), 6.4 – 7.4 (m), 7.65 (d),
8.09 (s), 8.15 (s). CI HRMS: calcd. for monomer 10, C15H16N2O
241.1340, found 241.1345. A sample (20 mg) was dissolved in
TFA to form the monomer.TFA salt: 1H NMR (400 MHz, TFA):
ꢀ 0.95 – 1.67 (m, 6H), 2.76 (brt J = 12 Hz 1H), 2.85 (d, J = 18

Nov-Dec 2007
A Novel Synthesis of (±)-Harmacine
1463
1.73 (m 2H), 2.84 (brd, J = 13 Hz, 1H), 2.32 (brd, J = 12.8 Hz,
1H), 2.65 (dt, J = 2.4, 12.8 Hz, 1H), 3.54 (d, J = 2.8 Hz, 2H),
4.66 (brd, J = 11 Hz, 1H), 4.76 (brd, J = 11 Hz), 6.99 (t, J = 8
Hz, 1H), 7.09 (t, J = 8 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.41 (d, J
= 8 Hz, 1H), 11.00 (s, 1H); 13C NMR and DEPT (75 MHz,
CDCl3/d6-DMSO): ꢀ 24.1 (CH2), 25.1 (CH2), 29.1 (CH2), 34.1
(CH2), 42.9 (CH2), 56.3 (CH), 102.8 (C), 111.0 (CH), 117.7
(CH), 118.8 (CH), 121.4 (CH), 125.4 (C), 130.7 (C), 136.7 (C),
166.5 (C). HRMS: calcd. for C15H16N2O 241.1340, found
241.1347
Method B: A solution of (8) (1.77 g, 0.005 mol) and
trifluoromethanesulfonic acid (0.6 mL, 0.0068 mol) in
dioxan (50 mL) was heated under reflux for 2 h. Isolation
of the product as described in Method A gave the lactam
(6) (0.56 g, 47%).
Acknowledgment. I am grateful to the GSK Neurology & GI
CEDD for funding this research, to J. Seaman for assistance
with the NMR assignment of 9b and to Prof. S. Caddick for his
support and the use of his laboratory at UCL.
REFERENCES
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Synthesis of (±)1,2,3,4,6,7,12,12b-octahydro-indole[2,3-a]-
quinolizine (4). Following the procedure, Method A, described
for (3), (6) (0.30 g, 0.0013 mol) was reduced with alane
prepared from LAH (2 mL of a 1M solution) to give (4) as a
pale yellow solid (0.20 g, 71%) mpt 148-150° (lit. 147-150°
[13]). 1H NMR (400 MHz, CDCl3): ꢀ 1.45 – 1.63 (m, 2H), 1.68-
1.78 (m, 2H), 1.91 (brd, J = 9 Hz, 1H), 2.07 (brd, J = 9 Hz, 1H),
2.39 (dt, J = 3, 11 Hz, 1H), 2.59 – 2.75 (m, 2H), 2.97 – 3.09 (m,
3H), 3.24 (d, J = 10 Hz), 7.06 – 7.15 (m, 2H), 7.30 (d, J = 7.6
Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H); 13C NMR and
DEPT (75 MHz, CDCl3): ꢀ 21.6 (CH2), 24.3 (CH2), 25.8 (CH2),
30.0 (CH2), 53.6 (CH2), 55.8 (CH2), 60.3 (CH), 108.2 (C), 110.7
(CH), 118.1 (CH), 119.4 (CH), 121.3 (CH), 127.5 (C), 135.1
(C), 136.0 (C).
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[9] The author thanks Rhodia Pharma Solutions Ltd. for the kind
gift of 4-chlorobutyraldehyde diethyl acetal.
[10] Fritz, H.; Pfaender, P. Chem. Ber., 1965, 98, 989.
[11] Jackson, A.H.; Naidoo, B. Tetrahedron, 1969, 25, 4843.
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