Rapid synthesis of the tetrahydroquinoline alkaloids: angustureine, cuspareine and galipinine

Article abstract of DOI:10.1016/j.tet.2008.06.073

A one-pot method for the preparation of 1,2-substituted dihydroquinolines is described. This method features the C-2 addition of a range of organolithium reagents to quinoline followed by the in-situ addition of an electrophile. Standard palladium-catalys

Full text of DOI:10.1016/j.tet.2008.06.073

Tetrahedron 64 (2008) 8067–8072
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Rapid synthesis of the tetrahydroquinoline alkaloids: angustureine,
cuspareine and galipinine
*
Aisling O’Byrne, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2008
Received in revised form 4 June 2008
Accepted 19 June 2008
Available online 24 June 2008
A one-pot method for the preparation of 1,2-substituted dihydroquinolines is described. This method
features the C-2 addition of a range of organolithium reagents to quinoline followed by the in-situ ad-
dition of an electrophile. Standard palladium-catalysed hydrogenation, of the resultant 1,2-disubstituted
dihydroquinoline adducts, generates the corresponding 1,2-disubstituted tetrahydroquinoline. A series of
such compounds have been synthesised including the natural products; (ꢀ)-angustureine 1, cuspareine 2
and galipinine 3.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Tetrahydroquinoline
Organolithium
Natural product
Anti-malarial
1. Introduction
undergo efficient in-situ alkylation, on addition of an external
electrophile.6 Subsequent palladium-catalysed hydrogenation of
Tetrahydroquinoline derivatives continue to attract interest due
to their importance as synthetic intermediates and as the key
structural element in several natural products. One such family of
optically active 1-methyl-2-alkyl tetrahydroquinolines 1–4 (Fig. 1)
has recently been isolated from Galipea officinalis Hancock, a Ven-
ezuelan shrubby tree.1 A preparation made from this tree, com-
monly called angostura, is acclaimed in the area of folk medicine
principally to combat fevers.1,2 This study also demonstrated that
individual members of the family of natural products, particularly
galipinine 3, exhibit promising activities against the malaria dis-
ease causing parasite, Plasmodium falciparum.1a
Over the years several synthetic routes have been devised for
the preparation of this type of 2-substituted tetrahydroquinoline.3
Asymmetric approaches have, more recently, been described for
the preparation of 1, 2 and 3, which have enabled the absolute
stereochemistry of the single stereogenic centre present in the
naturally occurring compounds to be determined.4 We envisaged
that such 1,2-disubstituted tetrahydroquinoline alkaloids could be
readily synthesised by the reaction of quinoline 5 with an organo-
metallic reagent, followed by the addition of an alkyl halide
the dihydroquinoline product of this reaction would generate the
desired 1,2-disubstituted tetrahydroquinoline structural motif.
2. Results and discussion
As illustrated in Scheme 1, in order to investigate the feasibility
of this sequence for the synthesis of 1–4 we began by exploring
a range of suitable organometallic reagents. Thus, a solution of
quinoline 5 in THFy was treated with the various organolithium
reagentsz followed by addition of the appropriate electrophile. The
nucleophilic C-2 addition step was monitored by TLC and on con-
sumption of the starting material 5 the electrophile was directly
added to the solution of the lithium anilide.
In the case of aqueous ammonium chloride (entry 1), in addition
to the expected dihydroquinoline a small amount of the re-oxidised
2-butylquinoline 13 was also observed. Subsequent treatment of
this mixture under standard reduction conditions gave a separable
mixture of 2-butyltetrahydroquinoline 6 (84%) and 13 (14%). Simi-
larly, the use of methyliodide gave good yields of the adduct 7
following the three-step reaction sequence (entry 2). Use of benzyl
bromide (entry 3) gave good conversion forming the corresponding
electrophile. It has long been appreciated that
p-poor aromatic
heterocycles, such as 5, are susceptible to nucleophilic addition.5
Additionally, it has recently been shown that such adducts may
y
The use of diethylether for this one-pot process in the place of THF proved, in
some instances, to be problematic due to the insolubility of the intermediate lith-
ium anilide in this solvent.
z
* Corresponding author.
Addition of n-butylmagnesium chloride to 5 under these conditions does not
E-mail address: paul.evans@ucd.ie (P. Evans).
proceed to completion; see also Ref. 6a.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.073

8068
A. O’Byrne, P. Evans / Tetrahedron 64 (2008) 8067–8072
(2) reduction
OR
N
N
(1a) C-2 addition
Me
1
Me
2 - 4
N
OR'
(1b) N-alkylation
5
( )-Angustureine 1
( )-Cuspareine 2: R = R' = Me;
( )-Galipinine 3: R = R' = CH2;
( )-Galipeine 4: R = OH; R' = Me
Figure 1. Representative tetrahydroquinoline natural products 1–4 and their retrosynthesis based on the one-pot C-2 nucleophilic additiondN-alkylation of quinoline 5.
dihydroquinoline, however, on hydrogenolysis significant cleavage
of the N-benzylic bond was also observed, forming 6 (36%) in
addition to the N-benzyl target compound 8 (55%). Attempts to
optimise this reaction further by altering the catalyst loading and
reaction times were not successful. The use of 1-bromo-2-meth-
ylpropane (entry 4) made a significant difference to the overall
efficiency of the one-pot procedure. The desired 1,2-adduct, 9, was
only isolated in 17% overall yield and in addition 6 (22%) and 2-
butylquinoline 13 (51%) were separated following purification by
flash column chromatography. This finding is presumably
explained by the diminished reactivity of this particular alkylating
reagent. The use of alternative, commercially available, organo-
lithium reagents, t-BuLi, MeLi and PhLi (entries 5–7), gave the
products from the hoped-for reaction sequence. In the case of t-
BuLi (entry 5) it was necessary to conduct the reaction initially at
ꢁ78 ꢂC in order to minimise its non-productive reaction with the
solvent. Also of note was the observation that adduct 12 was iso-
lated in reasonable yield (69%) indicating that, in this instance, in
contrast to entry 3, benzylic carbon–nitrogen bond cleavage did not
significantly occur (entry 7).
Having verified the versatility of the method, we desired to
employ this approach for the synthesis of the naturally occurring
1,2-dialkyltetrahydroquinoline compounds 1–3. In the case of
angustureine 1 (Scheme 1, entry 8), n-pentyllithium was generated
from n-pentylbromide and lithium metal in pentane.7 This reagent
was then added to quinoline 5 in THF under nitrogen at 0 ꢂC. Fol-
lowing complete formation of the 2-substituted anilide, methyl-
iodide was added. As above, the resultant dihydroquinoline was
then converted to angustureine 1 in 90% yield (three-steps) fol-
lowing palladium-catalysed hydrogenation.
was based on a report by Lee et al.8 and using this method trans-
vinyl bromides 17 and 19 were prepared in approximately 50%
yields from the respective, commercially available, cinnamic acids
15 and 16 (Scheme 2).
Although the preparation of 17 and 19, under the conditions
indicated, proved to be E-stereoselective, in our hands we observed
the formation of a more polar by-product. On analysis these im-
purities proved to be compounds 18 and 20, which presumably
arise from the further conversion of the trans-vinyl bromides 17
and 19 under the reaction conditions.9 This hypothesis was cor-
roborated by the observation that a purified sample of 17 un-
derwent efficient conversion to 18 under identical reaction
conditions.
Lithiation of vinyl bromides 17 and 19 was achieved using tert-
butyllithium in diethylether at ꢁ78 ꢂC. In relation to this lithium-
bromide exchange process it was found to be important to use
2 equiv of t-BuLi in order to minimise formation of protonated
styrene by-products. Subsequent addition of the lithium species to
quinoline 5 in THF at room temperature gave the anilide, which, on
addition of methyliodide gave 21 and 22. Flash column chroma-
tography was employed to remove excess quinoline 5 and the
resulting dihydroquinoline adducts were each reduced with hy-
drogen (1 atm) using palladium as a catalyst. In relation to this
transformation, it was found that under these conditions the
endocyclic, dihydroquinoline, double bond undergoes conversion
significantly more rapidly than the exocyclic, styrenyl alkene. In
this manner (ꢀ)-2 and (ꢀ)-3 were formed in 52% and 58% yields,
respectively, over the four-steps.
Based on the report by Alexakis and co-workers,6a we briefly
investigated whether the inclusion of the diamine, (ꢁ)-sparteine,
influenced the one-pot process in an asymmetric sense. This was
investigated for the synthesis of galipinine 3 in two approaches;
firstly (ꢁ)-sparteine was pre-mixed with quinoline 5 in THF before
The construction of cuspareine 2 and galipinine 3 presented
a greater challenge since the requisite organometallic precursor
was not commercially available. Our approach to these compounds
(2) H2,
Pd/C
(1a) RLi;
(1b) E
N
E
R
N
E
R
N
R
N
5
6: R = n-Bu; E = H;
13: R = n-Bu;
7: R = n-Bu; E = Me; 14: R = n-Pent
8: R = n-Bu; E = Bn;
9: R = n-Bu; E = i-Bu;
10: R = t-Bu; E = Me;
11: R = Me; E = Me;
12: R = Ph; E = Me;
1: R = n-Pent; E = Me
Product (%)a
Entry
R
E
H (NH4Cl(aq)) 6 (84%); 13 (14%)
Me (MeI) 7 (86%)
n-Bu Bn (BnBr) 8 (55%); 6 (36%)
n-Bu i-Bu (i-BuBr) 9 (17%); 6 (22%); 13 (51%)
1
2
3
4
5b
6
7
8
n-Bu
n-Bu
t-Bu
Me
Ph
Me (MeI) 10 (84%)
Me (MeI) 11 (67%)
Me (MeI) 12 (69%)
n-Pent Me (MeI) 1(90%); 14 (6%)
Cond. (1a) RLi (1.5 - 2 equiv.), THF, 0 °C; (1b) E , 0 °C; (2) H2, Pd/C (10 mol%), EtOH;
aIsolated yield over 3-steps following purification by flash column chromatography;
b
t-BuLi was added at -78 ºC and then warmed to 0 °C
Scheme 1.

A. O’Byrne, P. Evans / Tetrahedron 64 (2008) 8067–8072
8069
OH
NaBr, oxone,
Na2CO3, rt;
HO2C
OR
OR
Br
OR
OR
Br
OR
OR
+
Br
MeCN-H2O (3:2)
15: R = Me;
16: R = CH2
17: R = Me; 51%;
19: R = CH2; 50%
18: R = Me; 34%;
20: R = CH2; 48%
(1) t-BuLi, Et2O,
-78 ºC to 0 ºC;
H2, Pd/C,
EtOH, rt
OR
OR
17: R = Me;
19: R = CH2
2: R = Me; 52%;
3: R = CH2, 58%
N
Me
(2) 5, THF, 0 ºC;
(3) MeI, 0 ºC;
21: R = Me;
22: R = CH2
Scheme 2.
addition of the vinyl lithium reagent derived from 19 at 0 ꢂC.
Methyliodide was then added and the reaction finally quenched. In
this case 3 was obtained in 20% eex following reduction. In an al-
ternative process (ꢁ)-sparteine was initially added to the vinyl
bromide 19 at ꢁ78 ꢂC, which was then treated with t-BuLi. Sub-
sequent addition to quinoline 5 ultimately provided an enantio-
meric excess of 13% ee for 3. In both these unoptimised examples
preferential formation of the unnatural (þ)-isomer of 3 occurred.
In conclusion, we have developed an efficient three-step, two-
pot procedure for the synthesis of racemic 1,2-dialkyl substituted
tetrahydroquinolines. Typically these compounds were obtained in
moderate to good overall yields and the examples chosen represent
the versatility of this reaction with regards to both the organo-
lithium reagent and the electrophile. This approach has been suc-
cessfully applied to the synthesis of the tetrahydroquinoline
alkaloids, angustureine 1, cuspareine 2 and galipinine 3 featuring
the use of functionalised, styryl organometallic species that have
not been described previously.
Purification, finally, by flash column chromatography afforded the
desired 1,2-disubstituted tetrahydroquinoline.
3.3. 2-Butyl-1,2,3,4-tetrahydroquinoline 6
Following the above procedure, quinoline
5
(0.30 mL,
2.54 mmol) was converted into 6 (401 mg, 84%) with a 1.6 M so-
lution of n-BuLi in hexanes (2.40 mL, 3.81 mmol) and quenching
with a saturated aqueous ammonium chloride solution (20 mL).
The title compound was isolated after flash column chromatography
(cyclohexane–EtOAc; 19:1) as a yellow oil. Rf¼0.5 (cyclohexane–
EtOAc; 19:1); nmax (neat/cmꢁ1) 3016, 2927, 2857, 1605, 1491, 1352,
1310, 1273, 1126, 1077, 927, 829, 746, 659; dH (400 MHz, CDCl3) 0.93
(3H, t, J¼7.0 Hz, CH3), 1.33–1.40 (4H, m, CH2), 1.47–1.52 (2H, m,
CH2), 1.54–1.64 (1H, m, CH2-3), 1.94–1.99 (1H, m, CH2-3), 2.69–2.84
(2H, m, CH2-4), 3.20–3.26 (1H, m, CH-2), 3.75 (1H, br s, NH), 6.46
(1H, dd, J¼1.0, 8.5 Hz, ArH), 6.59 (1H, dd, J¼1.0, 7.5 Hz, ArH), 6.93–
7.00 (2H, m, ArH); dC (100 MHz, CDCl3) 14.0 (CH3), 22.8 (CH2), 26.4
(CH2), 27.9 (CH2), 28.1 (CH2), 36.4 (CH2), 51.6 (CH), 114.0 (CH), 116.9
(CH), 121.4 (C), 126.7 (CH), 129.2 (CH), 144.7 (C); HRMS calcd for
3. Experimental
3.1. General
C
13H20N (Mþ1) requires 190.1596; found 190.1587. Further elution
gave 2-butylquinoline 13 (67 mg, 14%) as a yellow oil;10 Rf¼0.3
(cyclohexane–EtOAc; 19:1); nmax (neat/cmꢁ1) 3196, 3053, 2954,
2823, 1602, 1561, 1504, 1460, 1309; dH (400 MHz, CDCl3) 0.96 (3H, t,
J¼7.5 Hz, CH3), 1.46 (2H, sex, J¼7.5 Hz, CH2), 1.76–1.84 (2H, m, CH2),
2.98 (2H, t, J¼8.0 Hz, CH2), 7.30 (1H, d, J¼8.5 Hz, ArH), 7.40–7.46
(1H, m, ArH), 7.66–7.70 (1H, m, ArH), 7.77 (1H, dd, J¼1.0, 8.5 Hz,
ArH), 8.03–8.07 (2H, m, ArH); dC (100 MHz, CDCl3) 13.9 (CH3), 22.7
(CH2), 32.2 (CH2), 39.1 (CH2), 121.4 (CH), 125.6 (CH), 126.7 (C), 127.5
(CH), 128.8 (CH), 129.3 (CH), 136.2 (CH), 147.9 (C), 163.1 (C); HRMS
calcd for C13H16N (Mþ1) requires 186.1283; found 186.1282.
Tetrahydrofuran (THF) was freshly distilled from sodium-ben-
zophenone prior to use. Quinoline 5 was dried over MgSO4 and
distilled under reduced pressure (15 mmHg) prior to use. All other
reagents were obtained from commercial sources and used without
further purification.
3.2. General procedure for the one-pot C-2 additiondN-
functionalisation of quinoline 5
Under nitrogen at 0 ꢂC a solution of quinoline 5 (0.30 mL,
2.54 mmol,1 equiv) inTHF (20 mL) was treated with the appropriate
organolithium reagent (3.81 mmol, 1.5 equiv). Stirring was contin-
ued for 0.5 h whereupon TLC analysis indicated the consumption of
starting material. The electrophile (5.08 mmol, 2 equiv) was then
added dropwise and stirring maintained for 2 h. Saturated aqueous
NH4Cl (20 mL) and dichloromethane (20 mL) were added and the
resultant aqueous layer was further extracted with dichloro-
methane (2ꢃ20 mL). The combined organic layers were dried over
MgSO4, filtered and the solvent removed under reduced pressure.
The crude dihydroquinoline product was dissolved in EtOH (20 mL)
and 10% w/w Pd/C (270 mg, ca. 10 mol %) was added before the
mixture was stirred under H2 (ca. 1 atm) for 24 h. The reaction
mixture was then filtered through Celite, washing with EtOAc
(2ꢃ20 mL) and the solvent removed under reduced pressure.
3.4. 1-Methyl-2-butyl-1,2,3,4-tetrahydroquinoline 7
Following the above procedure, quinoline
5
(0.30 mL,
2.54 mmol) was converted into 7 (444 mg, 86%) with a 1.6 M so-
lution of n-BuLi in hexanes (2.40 mL, 3.81 mmol) and subsequent
reaction with methyliodide (0.32 mL, 5.08 mmol). The title com-
pound was isolated after flash column chromatography (cyclohex-
ane–EtOAc; 19:1) as a yellow oil. Rf¼0.8 (cyclohexane–EtOAc; 9:1);
nmax (neat/cmꢁ1) 3066, 2930, 2929, 2870, 2799, 1603, 1578, 1500,
1452, 1380, 1334, 1274, 1215, 1091, 1051; dH (400 MHz, CDCl3) 0.99
(3H, t, J¼6.5 Hz, CH3), 1.29–1.53 (5H, m, CH2), 1.66–1.72 (1H, m,
CH2),1.91–1.98 (2H, m, CH2-3), 2.73 (1H, ddd, app. dt, J¼4.0,16.5 Hz,
CH2-4), 2.84–2.92 (1H, m, CH2-4), 3.00 (3H, s, CH3), 3.28–3.33 (1H,
m, CH-2), 6.60 (1H, d, J¼7.5 Hz, ArH), 6.66 (1H, t, J¼7.5 Hz, ArH),
7.04 (1H, d, J¼7.5 Hz, ArH), 7.25 (1H, t, J¼7.5 Hz, ArH); dC (100 MHz,
CDCl3) 14.1 (CH3), 22.9 (CH2), 23.5 (CH2), 24.4 (CH2), 28.3 (CH2),
30.9 (CH2), 37.9 (CH3), 58.9 (CH), 110.3 (CH), 115.1 (CH), 121.8 (C),
127.0 (CH), 128.6 (CH), 145.3 (C); HRMS calcd for C14H22N (Mþ1)
x
The enantiomeric excess was determined by chiral HPLC according to Ref. 4c.

8070
A. O’Byrne, P. Evans / Tetrahedron 64 (2008) 8067–8072
requires 204.1752; found 204.1743; Anal. Calcd for C14H12N: C,
82.70; H, 10.41; N, 6.89%; found: C, 82.42; H, 10.26; N, 6.76%.
requires 204.1752; found 204.1743; Anal. Calcd for C14H12N: C,
82.70; H, 10.41; N, 6.89%; found: C, 82.47; H, 10.28; N, 6.63%.
3.5. 1-Benzyl-2-butyl-1,2,3,4-tetrahydroquinoline 8
3.8. 1,2-Dimethyl-1,2,3,4-tetrahydroquinoline 113a
Following the above procedure, quinoline
5
(0.30 mL,
Following the above procedure, quinoline
5
(0.30 mL,
2.54 mmol) was converted into 8 (390 mg, 55%) with a 1.6 M so-
lution of n-BuLi in hexanes (2.40 mL, 3.81 mmol) and subsequent
reaction with benzyl bromide (0.61 mL, 5.08 mmol). The title com-
pound was isolated after flash column chromatography (cyclo-
hexane–EtOAc; 19:1) as a yellow oil. Rf¼0.4 (cyclohexane–EtOAc;
19:1); nmax (neat/cmꢁ1) 3025, 2928, 2858, 1602, 1498, 1454, 1212,
1174, 1064, 926; dH (400 MHz, CDCl3) 0.88 (3H, t, J¼7.0 Hz, CH3),
1.16–1.35 (5H, m, CH2), 1.47–1.64 (1H, m, CH2), 1.93–2.00 (2H, m,
CH2-3), 2.70 (1H, dt, J¼4.0, 16.0 Hz, CH2-4), 2.84–2.90 (1H, m, CH2-
4), 2.92 (2H, s, CH2), 3.32–3.37 (1H, m, CH-2), 6.38 (1H, d, J¼8.0 Hz,
ArH), 6.55 (1H, t, J¼8.0 Hz, ArH), 6.93 (1H, t, J¼8.0 Hz, ArH), 7.00 (1H,
d, J¼8.0 Hz, ArH), 7.17–7.20 (5H, m, ArH); dC (100 MHz, CDCl3) 14.1
(CH3), 22.8 (CH2), 23.6 (CH2), 24.2 (CH2), 28.3 (CH2), 31.7 (CH2), 37.9
(CH2), 57.8 (CH), 111.4 (CH), 115.3 (CH), 121.6 (C), 127.0 (CH), 128.3
(CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 141.8 (C), 144.5 (C); HRMS
calcd for C20H26N (Mþ1) requires 280.2065; found 280.2054. On
further elution 6 (171 mg, 36%) was also isolated whose data cor-
responded with that reported above.
2.54 mmol) was converted into 11 (274 mg, 67%) on treatment with
a 1.6 M solution of MeLi in diethylether (2.40 mL, 3.81 mmol). The
title compound was isolated after flash column chromatography
(cyclohexane–EtOAc; 19:1) as a yellow oil. Rf¼0.5 (cyclohexane–
EtOAc; 9:1); nmax (neat/cmꢁ1) 3067, 3019, 2965, 2930, 2870, 2846,
2826, 1668, 1603, 1576, 1499, 1479, 1455, 1373, 1328, 1305, 1275,
1216, 1162, 1137, 1121, 1084, 1048, 1034; dH (400 MHz, CDCl3) 1.15
(3H, d, J¼6.5 Hz, CH3), 1.73–1.81 (1H, m, CH2-3), 1.94–2.06 (1H, m,
CH2-3), 2.66–2.74 (1H, m, CH2-4), 2.80–2.87 (1H, m, CH2-4), 2.91
(3H, s, CH3), 3.41–3.50 (1H, m, CH-2), 6.55–6.63 (2H, m, ArH), 6.98
(1H, d, J¼7.5 Hz, ArH), 7.10 (1H, t, J¼7.5 Hz, ArH); dC (100 MHz,
CDCl3) 17.6 (CH3), 23.8 (CH2), 28.1 (CH2), 37.0 (CH3), 53.8 (CH), 110.6
(CH), 115.4 (CH), 122.6 (C), 127.1 (CH), 128.5 (CH), 145.4 (C); HRMS
calcd for C11H16N (Mþ1) requires 162.1283; found 162.1286.
3.9. 1-Methyl-2-phenyl-1,2,3,4-tetrahydroquinoline 12
According to the general procedure quinoline 5 (0.30 mL,
2.54 mmol) in THF (20 mL) was treated with a 1.8 M solution of
phenyllithium in di-n-butylether (2.11 mL, 3.81 mmol). Methyl-
iodide (0.32 mL, 5.08 mmol, 2 equiv) was then added. The crude
product (636 mg) was then dissolved in EtOH (20 mL), 10% w/w Pd/
C (270 mg, ca. 10 mol %) was added and the reaction was stirred
under H2 (ca. 1 atm) for 24 h. Purification by flash column chro-
matography (cyclohexane–EtOAc; 99:1) afforded 12 (391 mg, 69%)
as a white solid. Rf¼0.6 (cyclohexane–EtOAc; 9:1); mp 98–99 ꢂC [lit.
mp 102 ꢂC (MeOH–H2O)];11 nmax (neat/cmꢁ1) 3027, 2928, 2894,
2834,1882,1600,1577,1499,1448,1379, 1341,1311,1222,1176,1129,
1073; dH (400 MHz, CDCl3) 1.99–2.08 (1H, m, CH2-3), 2.17–2.28 (1H,
m, CH2-3), 2.60–2.69 (2H, m, CH2-4), 4.51 (1H, t, J¼4.5 Hz, CH-2),
6.68 (2H, app. quartet, J¼7.5 Hz, ArH), 7.01 (1H, d, J¼7.5 Hz, ArH),
7.16–7.37 (6H, m, ArH); dC (100 MHz, CDCl3) 24.2 (CH2), 30.1 (CH2),
37.7 (CH3), 63.2 (CH), 109.9 (CH), 115.5 (CH), 122.6 (C), 126.5 (CH),
126.8 (CH), 127.3 (CH), 128.3 (CH), 128.4 (CH), 144.3 (C), 146.1 (C);
HRMS calcd for C16H18N (Mþ1) requires 224.1439; found 224.1429.
3.6. 1-iso-Butyl-2-butyl-1,2,3,4-tetrahydroquinoline 9
Following the above procedure, quinoline
5
(0.30 mL,
2.54 mmol) was converted into 9 (107 mg, 17%) on treatment with
a 1.6 M solution of n-BuLi in hexanes (2.40 mL, 3.81 mmol) and
subsequent reaction with iso-butyl bromide (0.55 mL, 5.08 mmol).
The title compound was isolated after flash column chromatography
(cyclohexane–EtOAc; 19:1) as a yellow oil. Rf¼0.6 (cyclohexane–
EtOAc; 19:1); nmax (neat/cmꢁ1) 3019, 2952, 2865, 1499, 1344, 1254,
1212, 1098, 1057, 1002, 910; dH (400 MHz, CDCl3) 0.89–0.97 (9H, m,
CH3), 1.21–1.47 (5H, m, CH2), 1.51–1.60 (1H, m, CH2), 1.89–1.94 (2H,
m, CH2-3), 2.04–2.12 (1H, m, CH), 2.64–2.70 (2H, m, CH2-4, CH2),
2.82–2.91 (1H, m, CH2-4), 3.25–3.30 (1H, m, CH-2), 3.40 (1H, dd,
J¼4.5, 18.5 Hz, CH2), 6.51 (1H, d, J¼8.0 Hz, ArH), 6.55 (1H, t,
J¼8.0 Hz, ArH), 6.99 (1H, d, J¼8.0 Hz, ArH), 7.04 (1H, t, J¼8.0 Hz,
ArH); dC (100 MHz, CDCl3) 14.1 (CH3), 20.2 (CH3), 20.5 (CH3), 22.9
(CH2), 23.1 (CH2), 23.7 (CH2), 26.6 (CH), 28.4 (CH2), 30.7 (CH2), 58.4
(CH), 58.5 (CH2), 110.8 (CH), 114.5 (CH), 121.0 (C), 126.8 (CH), 129.2
(CH), 144.3 (C); HRMS calcd for C17H28N (Mþ1) requires 246.2222;
found 246.2215. Further elution gave initially 6 (139 mg, 29%) then
13 (240 mg, 51%) whose data was as above.
3.10. n-Pentyllithium7
At room temperature, under nitrogen, 1-bromopentane (1.5 mL,
12.1 mmol, 1 equiv) was added dropwise over ca. 10 min to small
pieces of lithium foil (176 mg, 25.4 mmol, 2.1 equiv) rapidly stirred
in pentane (20 mL). The mixture was stirred at room temperature
for 1.5 h and used directly.
3.7. 1-Methyl-2-tert-butyl-1,2,3,4-tetrahydroquinoline 10
Following the above procedure, quinoline
2.54 mmol) was converted into 10 (434 mg, 84%) on treatment with
1.7 M solution of tert-butyllithium in pentane (2.24 mL,
5
(0.30 mL,
3.11. 1-Methyl-2-pentyl-1,2-dihydroquinoline
a
3.81 mmol, 1.5 equiv) at ꢁ78 ꢂC. The reaction mixture was warmed
to 0 ꢂC over 1.5 h and methyliodide (0.32 mL, 5.08 mmol) was
added. Following hydrogenation as described the title compound
was isolated by flash column chromatography (cyclohexane–
EtOAc; 99:1) as a yellow oil. Rf¼0.6 (cyclohexane–EtOAc; 9:1); nmax
(neat/cmꢁ1) 3017, 2956, 2904, 2795, 1683, 1601, 1578, 1503, 1500,
1368, 1320, 1272, 1212, 1095, 1043, 930, 744; dH (400 MHz, CDCl3)
0.97 (9H, s, CH3), 1.85 (1H, app. septet, J¼7.5 Hz, CH2-3), 2.13–2.18
(1H, m, CH2-3), 2.70 (1H, dd, J¼5.0, 16.7 Hz, CH2-4), 2.85–2.94 (1H,
m, CH2-4), 3.00 (1H, dd, J¼2.5, 5.5 Hz, CH-2), 3.14 (3H, s, CH3), 6.60
(2H, app. t, J¼7.5 Hz, ArH), 6.97 (1H, d, J¼7.5 Hz, ArH), 7.11 (1H, t,
J¼7.5 Hz, ArH); dC (100 MHz, CDCl3) 22.9 (CH2), 24.8 (CH2), 28.6
(CH3), 38.3 (C), 43.8 (CH3), 67.7 (CH),111.4 (CH),115.0 (CH),121.8 (C),
126.8 (CH), 128.8 (CH), 146.7 (C); HRMS calcd for C14H22N (Mþ1)
Under nitrogen at 0 ꢂC a solution of quinoline 5 (0.57 mL,
4.80 mmol, 1 equiv) in THF (20 mL) was treated with the above
n-pentyllithium solution (10 mL, ca. 6.05 mmol, 1.25 equiv) and
stirred for 0.5 h. TLC analysis indicated consumption of starting
material. Methyliodide (0.70 mL, 11.24 mmol, 2.3 equiv) was added
dropwise and stirring was maintained for 2 h. Saturated aqueous
NH4Cl (20 mL) and dichloromethane (20 mL) were added and the
resultant aqueous layer was further extracted with dichloro-
methane (2ꢃ20 mL). The combined organic layers were dried over
MgSO4, filtered and the solvent removed under reduced pressure.
Purification by flash column chromatography (cyclohexane–EtOAc;
9:1) afforded the dihydroquinoline (923 mg, 89%) as a yellow oil.
Rf¼0.7 (cyclohexane–EtOAc; 9:1); nmax (neat/cmꢁ1) 3065, 3038,
2928, 2857, 1642, 1598, 1497; dH (500 MHz, CDCl3) 0.89 (3H, t,

A. O’Byrne, P. Evans / Tetrahedron 64 (2008) 8067–8072
8071
J¼6.5 Hz, CH3), 1.23–1.36 (6H, m, CH2), 1.45–1.52 (1H, m, CH2), 1.62–
1.69 (1H, m, CH2), 2.90 (3H, s, CH3), 4.03–4.06 (1H, m, CH-2), 5.69
(1H, dd, J¼5.5, 9.5 Hz, CH-3), 6.38 (1H, d, J¼9.5 Hz, CH-4), 6.43 (1H,
d, J¼7.5 Hz, ArH), 6.59 (1H, t, J¼7.5 Hz, ArH), 6.88 (1H, dd, J¼1.5,
7.5 Hz, ArH), 7.09 (1H, dt, J¼1.5, 7.5 Hz, ArH); dC (125 MHz, CDCl3)
14.1 (CH3), 22.6 (CH2), 23.8 (CH2), 32.1 (CH2), 33.9 (CH2), 36.4 (CH3),
60.7 (CH), 109.8 (CH), 116.1 (CH), 121.8 (C), 125.2 (CH), 125.7 (CH),
126.7 (CH), 129.0 (CH), 145.3 (C); HRMS calcd for C15H20N (Mꢁ1)
requires 214.1596; found 214.1585. Further elution gave 2-pentyl-
quinoline 1412 (55 mg, 6%) as a yellow oil. Rf¼0.6 (cyclohexane–
EtOAc; 9:1); dH (400 MHz, CDCl3) 0.78 (3H, t, J¼7.0 Hz, CH3),
1.22–1.30 (4H, m, CH2), 1.67 (2H, pent, J¼7.5 Hz, CH2), 2.85 (2H, t,
J¼7.5 Hz, CH2), 7.16 (1H, d, J¼8.5 Hz, CH-3), 7.34 (1H, t, J¼8.0 Hz,
ArH), 7.55 (1H, t, J¼8.0 Hz, ArH), 7.63 (1H, d, J¼8.0 Hz, ArH), 7.92
(1H, d, J¼8.5 Hz, CH-4), 7.94 (1H, d, J¼8.0 Hz, ArH); dC (100 MHz,
CDCl3) 13.9 (CH3), 22.5 (CH2), 29.5 (CH2), 31.7 (CH2), 39.2 (CH2),
121.3 (CH), 125.6 (CH), 126.6 (C), 127.4 (CH), 128.7 (CH), 129.3 (CH),
136.2 (CH), 147.7 (C), 163.0 (C); HRMS calcd for C14H18N (Mþ1)
requires 200.1439; found 200.1430.
3.87 (3H, s, CH3), 3.89 (3H, s, CH3), 4.98 (1H, d, J¼5.0, CH), 5.76 (1H,
d, J¼5.0 Hz, CH), 6.83–6.86 (1H, m, ArH), 6.93–6.96 (2H, m, ArH); dC
(100 MHz, CDCl3) 52.3 (CH), 55.9 (CH3), 56.0 (CH3), 78.8 (CH), 109.8
(CH), 110.8 (CH), 119.6 (CH), 130.4 (C), 149.0 (C), 149.5 (C); HRMS
calcd for
360.9045.
C10H12O3Br2Na (MþNa) requires 360.9051; found
3.14. trans-5-(2-Bromovinyl)benzo[d][1,3]dioxole 1913
trans-3-Benzo[1,3]dioxol-5-yl-acrylic acid 16 (1.15 g, 6.00 mmol,
1 equiv), sodium bromide (1.85 g, 18.00 mmol, 3 equiv), sodium
carbonate (0.63 g, 6.00 mmol, 1 equiv) and oxone (3.69 g,
6.00 mmol, 1 equiv) were dissolved in acetonitrile (60 mL) and H2O
(40 mL) and the reaction stirred for 3 h. EtOAc (50 mL) was added
and the aqueous and organic layers were separated. The aqueous
layer was further extracted with EtOAc (2ꢃ50 mL). The combined
organic layers were dried over MgSO4, filtered and the solvent re-
moved under reduced pressure. Purification by flash column
chromatography (cyclohexane–EtOAc; 15: 1) afforded the title
compound 19 (681 mg, 50%) as a white solid; mp 39–42 ꢂC; Rf¼0.7
(cyclohexane–EtOAc; 2:1); nmax (neat/cmꢁ1) 3074, 3011, 2896,
2779, 2694, 2601, 2443, 2361, 2205, 2045, 1855, 1612, 1586, 1503,
1489, 1446, 1351, 1250, 1212, 1184, 1122, 1101, 1039, 930, 859, 820,
795, 770, 739, 713, 682, 634, 602, 568, 529; dH (400 MHz, CDCl3)
5.96 (2H, s, CH2), 6.59 (1H, d, J¼14.0 Hz, CH), 6.74–6.75 (2H, m,
ArH), 6.80–6.81 (1H, m, ArH), 7.00 (1H, d, J¼14.0 Hz, CH); dC
(100 MHz, CDCl3) 101.2 (CH2), 104.5 (CH), 105.4 (CH), 108.4 (CH),
120.9 (CH), 130.3 (C), 136.7 (CH), 147.7 (C), 148.1 (C); HRMS cacld for
C9H7O2Br requires 225.9629; found 225.9621. Further elution gave
1-benzo[1,3]dioxol-5-yl-2,2-dibromoethanol 2014 (933 mg, 48%) as
3.12. 1-Methyl-2-pentyl-1,2,3,4-tetrahydroquinoline
(angustureine) 11b,4b
A mixture of 1-methyl-2-pentyl-1,2-dihydroquinoline (923 mg,
4.29 mmol, 1 equiv) and 10% w/w Pd/C (250 mg, ca. 5 mol %) in
EtOAc (25 mL) was stirred under hydrogen (ca. 1 atm) for 24 h. The
reaction mixture was filtered through Celite and washed with
EtOAc (2ꢃ25 mL). Solvent removal under reduced pressure gave
angustureine 1 (920 mg, 99%) as a yellow oil. Rf¼0.5 (cyclohexane–
EtOAc; 19:1); nmax (neat/cmꢁ1) 3022, 2931, 2859, 1602, 1500; dH
(500 MHz, CDCl3) 0.94 (3H, t, J¼7.0 Hz, CH3), 1.27–1.48 (7H, m, CH2),
1.60–1.67 (1H, m, CH2),1.90–1.94 (2H, m, CH2-3), 2.69 (1H, ddd, app.
dt, J¼4.5, 16.5 Hz, CH2-4), 2.84 (1H, ddd, J¼7.0, 10.5, 16.5 Hz, CH2-4),
2.96 (3H, s, CH3), 3.24–3.28 (1H, m, CH-2), 6.56 (1H, d, J¼7.5 Hz,
ArH), 6.61 (1H, t, J¼7.5 Hz, ArH), 6.99 (1H, d, J¼7.5 Hz, ArH), 7.11
(1H, t, J¼7.5 Hz, ArH); dC (125 MHz, CDCl3) 14.1 (CH3), 22.7 (CH2),
23.7 (CH2), 24.6 (CH2), 25.8 (CH2), 31.3 (CH2), 32.1 (CH2), 38.0 (CH3),
59.0 (CH), 110.5 (CH), 115.3 (CH), 122.0 (C), 127.1 (CH), 128.7 (CH),
145.5 (C); HRMS calcd for C15H24N (Mþ1) requires 218.1909; found
218.1898.
a yellow oil. Rf¼0.4 (cyclohexane–EtOAc; 2:1); nmax (neat/cmꢁ1
)
3482, 3076, 3006, 2901, 1730, 1681, 1604, 1504, 1489, 1445, 1357,
1248, 1143, 1096, 1038, 931; dH (400 MHz, CDCl3) 4.94 (1H, d,
J¼5.0 Hz, CH), 5.72 (1H, d, J¼5.0 Hz, CH), 5.98 (2H, s, CH2), 6.80 (1H,
d, J¼8.0 Hz, ArH), 6.87 (1H, dd, J¼1.5, 8.0 Hz, ArH), 6.92 (1H, d,
J¼1.5 Hz, ArH); dC (100 MHz, CDCl3) 55.1 (CH), 78.7 (CH), 101.3
(CH2), 107.2 (CH), 108.1 (CH), 120.8 (CH), 131.7 (C), 147.7 (C), 148.0
(C); Anal. Calcd for C9H8O3Br2: C, 33.37; H, 2.49%; found, C, 33.78; H,
2.56%.
3.15. 2-[2-(3,4-Dimethoxyphenyl)ethyl]-1-methyl-1,2,3,4-
tetrahydroquinoline (cuspareine) 22,4c
3.13. trans-4-(2-Bromovinyl)-1,2-dimethoxybenzene 179
trans-(3,4-Dimethoxy)cinnamic acid 15 (1.25 g, 6.00 mmol,
1 equiv), sodium bromide (1.85 g, 18.00 mmol, 3 equiv), sodium
carbonate (0.63 g, 6.00 mmol, 1 equiv) and oxone (3.69 g,
6.00 mmol, 1 equiv) were dissolved in acetonitrile (60 mL) and H2O
(40 mL) and the reaction stirred for 3 h. EtOAc (50 mL) was added.
The resultant organic layer was separated and the aqueous layer
was extracted with EtOAc (2ꢃ50 mL). The combined organic layers
were dried over MgSO4, filtered and the solvent removed under
reduced pressure. Purification by flash column chromatography
(cyclohexane–EtOAc; 15: 1) afforded the title compound 17 (741 mg,
51%) as a white solid; mp 48–50 ꢂC; Rf¼0.5 (cyclohexane–EtOAc;
2:1); nmax (neat/cmꢁ1) 3075, 3002, 2957, 2935, 2909, 2835, 1603,
1578, 1514, 1461, 1441, 1418, 1329, 1264, 1246, 1205, 1190, 1158, 1140,
1026, 941, 855, 813, 773; dH (300 MHz, CDCl3) 3.89 (3H, s, CH3), 3.91
(3H, s, CH3), 6.63 (1H, d, J¼14.0 Hz, CH), 6.80–6.87 (3H, m, ArH),
7.03 (1H, J¼14.0, CH); dC (100 MHz, CDCl3) 55.7 (CH3), 55.8 (CH3),
104.2 (CH), 108.5 (CH), 111.1 (CH), 119.3 (CH), 128.9 (C), 136.7 (CH),
149.0 (C), 149.2 (C); HRMS cacld for C10H11O2Br requires 241.9942;
found 241.9946. Further elution gave 2,2-dibromo-1-(3,4-dime-
thoxyphenyl)ethanol 18 (702 mg, 34%) as a white solid; mp 42–
43 ꢂC; Rf¼0.4 (cyclohexane–EtOAc; 2:1); nmax (neat/cmꢁ1) 3482,
3004, 2960, 2936, 2837, 2599, 1717, 1677, 1595, 1515, 1463, 1420,
1341, 1265, 1237, 1141, 1094, 1080, 1025, 962; dH (300 MHz, CDCl3)
trans-4-(2-Bromovinyl)-1,2-dimethoxybenzene
17
(1.00 g,
4.10 mmol, 1 equiv) was dissolved in diethylether (30 mL) under
nitrogen at ꢁ78 ꢂC. To this a 1.7 M solution of tert-butyllithium in
pentane (4.80 mL, 8.20 mmol, 2 equiv) was added and the reaction
stirred for 1 min. This solution was then added dropwise to quin-
oline 5 (0.48 mL, 4.10 mmol, 1 equiv) dissolved in THF (30 mL)
under nitrogen at room temperature. Stirring was maintained at
room temperature for 10 min, then the reaction was brought to 0 ꢂC
and methyliodide (0.51 mL, 8.20 mmol, 2 equiv) was added drop-
wise. Stirring was maintained for 2 h. Saturated aqueous NH4Cl
(50 mL) and dichloromethane (50 mL) were added and the re-
sultant aqueous layer was further extracted with dichloromethane
(2ꢃ50 mL). The combined organic layers were dried over MgSO4,
filtered and the solvent removed under reduced pressure. Excess
quinoline 5 was removed by flash column chromatography (cy-
clohexane–EtOAc; 30:1). The crude product 21 was then dissolved
in EtOH (80 mL) and 10% w/w Pd/C (435 mg, ca. 10 mol %) was
added, the reaction was stirred under H2 (ca. 1 atm) for 72 h. The
reaction mixture was then filtered through Celite and washed with
EtOAc (2ꢃ50 mL). The solvent was removed under reduced pres-
sure and purification by flash column chromatography (cyclohex-
ane–EtOAc; 99:1) afforded the title compound 2 (664 mg, 52%) as
a yellow oil. Rf¼0.5 (cyclohexane–EtOAc; 2:1); nmax (neat/cmꢁ1
)

8072
A. O’Byrne, P. Evans / Tetrahedron 64 (2008) 8067–8072
2933, 2838, 1601, 1508, 1456, 1331, 1262, 1148, 1029, 931, 851, 806,
745, 631; dH (600 MHz, CDCl3) 1.75–1.82 (1H, m, CH2-30), 1.94–2.02
(3H, m, CH2-3, CH2-30), 2.56–2.61 (1H, m, CH2-40), 2.69–2.76 (2H, m,
CH2-4, CH2-40), 2.87–2.93 (1H, m, CH2-4), 2.96 (3H, s, CH3), 3.31–
3.35 (1H, m, CH2-2), 3.88 (3H, s, CH3), 3.91 (3H, s, CH3), 6.58 (1H, d,
J¼7.5 Hz, ArH), 6.59 (1H, t, J¼7.5 Hz, ArH), 6.76–6.78 (2H, m, ArH),
6.83–6.85 (1H, m, ArH), 7.03 (1H, d, J¼7.5 Hz, ArH), 7.13–7.15 (1H, m,
ArH); dC (100 MHz, CDCl3) 23.5 (CH2), 24.3 (CH2), 31.8 (CH2), 33.0
(CH2), 38.0 (CH3), 55.7 (CH3), 55.8 (CH3), 58.3 (CH), 110.5 (CH), 111.3
(CH), 111.6 (CH), 115.3 (CH), 120.0 (CH), 121.6 (C), 127.0 (CH), 128.6
(CH), 134.6 (C), 145.2 (C), 147.2 (C), 148.8 (C); HRMS calcd for
(CH2), 24.3 (CH2), 31.9 (CH2), 33.1 (CH2), 38.0 (CH3), 58.1 (CH), 100.7
(CH2),108.1 (CH),108.6 (CH),110.6 (CH),115.4 (CH),120.8 (CH),121.7
(C), 127.0 (CH), 128.6 (CH), 135.8 (C), 145.2 (C), 145.6 (C), 147.6 (C);
HRMS calcd for
296.1637.
C
19H22NO2 (Mþ1) requires 296.1651; found
Acknowledgements
We wish to thank UCD for the provision of an Ad Astra post-
graduate scholarship (A.O’B.) and Mr. Christopher O’Byrne (Com-
munity School, Carrick-on-Shannon, Co. Leitrim) for the
preparation of 8 and 9.
C
20H26NO2 (Mþ1) requires 312.1964; found 312.1961.
3.16. 2-(2-Benzo[1,3]dioxol-5-ylethyl)-1-methyl-1,2,3,4-
tetrahydroquinoline (galipinine) 32,4c
References and notes
1. (a) Jacquemond-Collet, I.; Benoit-Vical, F.; Valentin, M. A.; Stanislas, E.; Mallie´,
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19
(1.00 g,
´
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butyllithium in pentane (5.20 mL, 8.80 mmol, 2 equiv) was added
and the reaction stirred for 1 min. This solution was then added
dropwise to quinoline (0.52 mL, 4.40 mmol, 1 equiv) dissolved in
THF (30 mL) under nitrogen at room temperature. Stirring was
maintained at room temperature for 10 min, then the reaction was
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was added dropwise. Stirring was maintained for 2 h. Saturated
aqueous NH4Cl (50 mL) and dichloromethane (50 mL) were added
and the resultant aqueous layer was further extracted with
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dried over MgSO4, filtered and the solvent removed under reduced
pressure. Unreacted quinoline 5 was removed by flash column
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22 was then dissolved in EtOH (80 mL) and 10% w/w Pd/C (468 mg,
ca. 10 mol %) was added, the reaction was stirred under H2 (ca.
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