Silver(i)-promoted oxidative cyclisation to pyrrolo[2,1-a]isoquinolines and application to the synthesis of (±)-crispine A

Article abstract of DOI:10.1039/c2ra22823h

The silver(i)-promoted oxidative cyclisation of 1-propargyl-substituted tetrahydroisoquinolines affords pyrrolo[2,1-a]isoquinolines. Scope and limitations of this method are described and an application to the synthesis of the natural product (±)-crispine A is presented. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ra22823h

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Silver(I)-promoted oxidative cyclisation to pyrrolo[2,1-
a]isoquinolines and application to the synthesis of ( )-
crispine A3{
Cite this: RSC Advances, 2013, 3,
1089
Sameer Agarwal, Olga Kataeva, Ulrike Schmidt and Hans-Joachim Knolker*
¨
Received 8th November 2012,
Accepted 15th November 2012
The silver(I)-promoted oxidative cyclisation of 1-propargyl-substituted tetrahydroisoquinolines affords
pyrrolo[2,1-a]isoquinolines. Scope and limitations of this method are described and an application to the
synthesis of the natural product (¡)-crispine A is presented.
DOI: 10.1039/c2ra22823h
www.rsc.org/advances
Introduction
Crispine A (1) and crispine B (2) (Fig. 1) are two natural
products isolated in 2002 by Zhao and co-workers from the
anti-tumor active extract of Carduus crispus L.1 The interesting
structure of the crispine alkaloids as well as their pharmaco-
logical potential led to a tremendous interest in these
compounds and thus, crispine A (1) has been synthesised
many times since its isolation.2–4 Interestingly, crispine A (1)
had already been synthesised long before its isolation as
natural product.5 However till now, only one synthesis has
been reported for crispine B (2).6 Recently, the development of
the different synthetic strategies towards crispine A (1) has
been summarised in a review which has appeared at the end of
last year.3 Since then, two additional new syntheses have been
reported.4
Fig. 1 Structures of crispine A (1) and crispine B (2).
In 2004, we reported a silver(I)-promoted oxidative 5-endo-
dig cyclisation to pyrroles.14,15 In the present paper, we
describe in full detail its application to the synthesis of
pyrrolo[2,1-a]isoquinolines including the natural product (¡)-
crispine A (1).2a Scope and limitations of this method are also
presented.
Due to their broad range of useful biological activities, the
synthesis and functionalisation of pyrroles has been in the
focus of heterocyclic chemists for a long time.7 Classical
approaches like the Hantzsch,8 the Knorr9 or the Paal–Knorr
synthesis10 have limitations with respect to functional group
compatibility and do not provide access to the full range of
substitution patterns. Therefore modern methods, often by
using transition metals, have been developed to provide
improved synthetic routes to pyrroles.11 In 1979, Claesson
and co-workers reported a silver-mediated cyclisation to
pyrroles.12 Since then various silver-promoted cyclisations
leading to pyrroles have been developed.13
Cyclisation to pyrrolo[2,1-a]isoquinolines
Addition of the propargyl Grignard reagents 4a–c to 3,4-
dihydroisoquinoline (3) following Nakagawa’s procedure (gen-
eration of a preformed BF3–imine complex)16 provided a
mixture of the 1-propargyl-1,2,3,4-tetrahydroisoquinolines 5
and the 1-allenyl-1,2,3,4-tetrahydroisoquinolines 6 (Scheme 1,
Table 1). The ratio of 5 to 6 is dependent on the nature of the
substituent R.
With the readily available 1-(3-trimethylsilylpropargyl)-
1,2,3,4-tetrahydroisoquinoline (5a) we have investigated the
cyclisation to a pyrrole ring by using various transition metal
salts (Scheme 2, Table 2). Platinum and gold salts, although
frequently used for cyclisations to pyrroles,11c did not lead to
significant amounts of product (Table 2, entries 1–3).
Palladium(II) acetate afforded the pyrrole 7a in a moderate
yield (Table 2, entry 4). With copper(II) acetate no product was
formed and only starting material was recovered, whereas in
the presence of copper(I) acetate the pyrrole 7a could be
obtained in 56% yield (Table 2, entries 5–6). Silver(I) is known
to generate silver(I)–(g2-alkyne) complexes,17 which leads to an
increase in reactivity of the alkyne towards nucleophilic attack.
¨
Department Chemie, Technische Universitat Dresden, Bergstrasse 66, 01069,
Dresden, Germany. E-mail: hans-joachim.knoelker@tu-dresden.de;
Fax: +49 351-463-37030
Part 107 of ‘Transition Metals in Organic Synthesis’; for Part 106, see: M. P.
3
¨
Krahl, O. Kataeva, A. W. Schmidt and H.-J. Knolker, Eur. J. Org. Chem., DOI:
10.1002/ejoc.201201251.
{ Electronic Supplementary Information (ESI) available: selected 1H and 13C
NMR spectra of 1–14. CCDC 873921. For ESI and crystallographic data in CIF or
other electronic format, see DOI: 10.1039/c2ra22823h
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Scheme 1 Addition of Grignard reagents 4a–c to 3,4-dihydroisoquinoline (3).
Reagents and conditions: (a) 1.0 equiv. BF3?OEt2, THF, 223 uC, 3.0 equiv. 4 in
Et2O, 15 h, Table 1.
Scheme 3 Cyclisation of the allenyl derivative 6a. Reagents and conditions: (a)
1.1 equiv. AgOAc, acetone, reflux, 14 h, 56%.
dihydropyrroles in a reaction which is catalytic in silver(I).18
Protodesilylation of 5a with tetrabutylammonium fluoride
(TBAF) afforded the unprotected alkyne 5d. Cyclisation of 5d
using the same reaction conditions as for 5a afforded a similar
yield of the pyrrole 7a (Table 2, entry 10). This result
demonstrated that the silver(I)-promoted oxidative cyclisation
can also be applied to terminal alkynes.
Table 1 Addition of Grignard reagents 4a–c to 3,4-dihydroisoquinoline (3)
4
R
5 + 6, Yield (%)
Ratio, 5 : 6
a
b
c
TMS
Me
Ph
90
66
19
8 : 1
1 : 10
1 : 1.5
The generation of a hexahydropyrrolo[2,1-a]isoquinoline
ring system as found in crispine A (1) required a chemoselec-
tive hydrogenation of the pyrrole ring of compound 7a. This
transformation was thought as a model study for the synthesis
of (¡)-crispine A (1). Methods for selective hydrogenation of
pyrroles have been described by Weinstein and
Muchowski.19,20 In fact, hydrogenation of compound 7a using
rhodium on activated carbon as catalyst provided
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (8) in 91%
yield (Scheme 2). Compound 8 has been known as a
degradation product of the alkaloid norsecurinone and is an
a2-adrenoreceptor antagonist.21,22 Several alternative routes to
8 have been reported.3 On treatment of the 1-allenyl-1,2,3,4-
tetrahydroisoquinoline 6a with stoichiometric amounts of
silver(I) acetate in dichloromethane at room temperature no
reaction took place and 90% of the starting material could be
re-isolated. However, application of slightly harsher reaction
conditions by heating of compound 6a in acetone at reflux for
14 h (procedure B) afforded the pyrrole 7a in 56% yield
(Scheme 3).
In fact, oxidative cyclisation of compound 5a by treatment with
stoichiometric amounts of silver(I) acetate in dichloromethane
at room temperature for 14 h (procedure A) provided the 5,6-
dihydropyrrolo[2,1-a]isoquinoline (7a) in 72% yield along with
metallic silver (Table 2, entry 7). An increase of the amount of
silver(I) acetate to 2.1 equivalents did not afford higher yields
(Table 2, entry 8). The oxidative cyclisation leads to an
aromatisation of the pyrrole ring by the generation of metallic
silver (for a discussion of the mechanism, see ref. 11c,14a,c).
Therefore, the reaction is not catalytic in silver(I) (Table 2,
entry 9). However, we have been able to show that an acceptor
group (e.g., p-tosyl) at the imine nitrogen prevents the
aromatisation step and leads to the formation of 2,3-
The optimised reaction conditions described above (proce-
dure A) for the silver(I)-promoted oxidative cyclisation have
also been applied to the methyl- and phenyl-substituted
propargyl compounds 5b, 5c and the allenyl compounds 6b,
6c (Scheme 4, Table 3). Interestingly, under these reaction
conditions, the pure propargyl compound 5b did not afford
exclusively 7b but also traces of 9b (Table 3, entry 1). The
corresponding allenyl compound 6b showed a similar iso-
merisation, even to a larger extent (Table 3, entry 2). The
methyl- and phenyl-substituted mixtures of the propargyl and
allenyl compounds 5b/6b and 5c/6c led to the corresponding
product mixtures 7b/9b and 7c/9c in moderate yields (Table 3,
entries 3–4). However, the phenyl-substituted allenyl com-
pound 6c afforded pure 1-phenyl-5,6-dihydropyrrolo[2,1-a]iso-
quinoline (9c) (Table 3, entry 5).
Scheme 2 Oxidative cyclisation to 5,6-dihydropyrrolo[2,1-a]isoquinoline (7a)
and chemoselective hydrogenation of the pyrrole ring. Reagents and conditions:
(a) transition metal salt, CH2Cl2, rt, 14 h, Table 2; (b) 1.0 equiv. TBAF, THF, rt, 3 h,
87%; (c) Rh/C (5%), H2, AcOH/MeOH (1 : 1), rt, 8 d, 91%.
Table 2 Oxidative cyclisation of the homopropargylamines 5a and 5d
Entry
R
Metal salt
Equiv.
7a, Yield (%)
1
2
3
4
5
6
7
8
9
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
H
PtCl2
Ph3PAuCl
AuCl
Pd(OAc)2
Cu(OAc)2
CuOAc
AgOAc
AgOAc
AgOAc
AgOAc
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.1
0.1
1.1
—
—
Traces
18
—
56
72
66
5
Synthesis of ( )-crispine A (1)
For the synthesis of (¡)-crispine A (1) via the method
described above, we required 6,7-dimethoxy-3,4-dihydroiso-
quinoline (11) as starting material (Scheme 5). Formylation of
the phenylethylamine 10 and subsequent Bischler–Napieralski
cyclisation following literature procedures afforded compound
10
71
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Fig. 2 Single crystal X-ray analysis of 8,9-dimethoxy-5,6-dihydropyrrolo[2,1-
a]isoquinoline (14).
Scheme 4 Silver(I)-promoted oxidative cyclisation of 5 and 6. Reagents and
conditions: (a) 1.1 equiv. AgOAc, CH2Cl2, rt, 14 h, Table 3.
into the dihydropyrroloisoquinoline 14 using the two different
sets of reaction conditions described above (procedures A and
B) for the silver(I)-promoted oxidative cyclisation. The struc-
ture of compound 14 has been unequivocally confirmed by an
X-ray crystal structure determination (Fig. 2). The rhodium-
catalysed hydrogenation of compound 14 provided (¡)-
crispine A (1). The present approach affords (¡)-crispine A
(1) in three steps and 24% overall yield based on the 3,4-
dihydroisoquinoline 11.
Table 3 Silver(I)-promoted oxidative cyclisation of the 1-propargyltetrahydro-
isoquinolines 5 and 1-allenyltetrahydroisoquinolines 6 to 7 and 9
Entry
R
5 : 6
Yield (%)
Ratio, 7 : 9
1
2
3
4
5
Me
Me
Me
Ph
1 : 0
0 : 1
1 : 10
1 : 1.5
0 : 1
38
34a
34
47
36
1 : Traces
1 : 6
1 : 10
1 : 1.5
0 : 1
Ph
Several attempts to transform (¡)-crispine A (1) into
crispine B (2) failed. Treatment with oxidising agents like
iodine, DDQ and manganese dioxide led to decomposition of
starting material. Dehydrogenation using catalytic amounts of
palladium on activated carbon in benzene at reflux led to
aromatisation of the tetrahydropyrrole and thus, regenerated
the 5,6-dihydropyrrolo[2,1-a]isoquinoline 14 in 88% yield
(Scheme 6). Suitable conditions to convert (¡)-crispine A (1)
into crispine B (2) could not be found.
a
Instead of CH2Cl2, Me2CO was used as solvent at room
temperature.
11 in 75% yield over both steps.23 Addition of trimethylsilyl-
propargylmagnesium bromide (4a) to the 3,4-dihydroisoquino-
line 11 provided a mixture of the 1-propargyltetrahydroiso-
quinoline 12 and the 1-allenyltetrahydroisoquinoline 13 (ratio
= 61 : 2) in 63% yield. Both products could be transformed
Conclusions
Using the silver(I)-promoted oxidative cyclisation of 1-propar-
gyl- and 1-allenyl-substituted tetrahydroisoquinolines, we have
developed a direct access to 5,6-dihydropyrrolo[2,1-a]isoqui-
nolines. Chemoselective hydrogenation of the pyrrole ring
leads to the corresponding hexahydropyrrolo[2,1-a]isoquino-
lines. The procedure opens up the way to a short synthesis of
the pyrrolo[2,1-a]isoquinoline alkaloid (¡)-crispine A (1).
Scheme 5 Synthesis of (¡)-crispine A (1). Reagents and conditions: (a) HCOOEt,
reflux, 12 h; (b) POCl3, 0 uC to rt, 3 h, 40 uC, 20 min, 75%, two steps; (c) 1.0 equiv.
BF3?OEt2, THF, 223 uC, 3.0 equiv. 4a in Et2O, 15 h, 61% 12, 2% 13; (d) 1.1 equiv.
AgOAc, CH2Cl2, rt, 14 h, 58%; (e) 1.1 equiv. AgOAc, acetone, reflux, 6 h, 43%; (f)
Rh/C (5%), H2, AcOH/MeOH (1 : 1), rt, 8 d, 66%.
Scheme 6 Dehydrogenation of (¡)-crispine A (1). Reagents and conditions: (a)
Pd/C, benzene, reflux, 12 h, 88%.
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87.21 (C), 104.66 (C), 125.80 (CH), 126.37 (CH), 126.51 (CH),
129.36 (CH), 135.46 (C), 137.55 (C). MS (25 uC): m/z (%) = 244
(3, [M + 1]+), 228 (6), 133 (30), 132 (100), 131 (4), 130 (13), 117
(15), 105 (10). HRMS: m/z calcd for C15H22NSi [M + 1]+:
244.1522, found: 244.1498.
Experimental section
General
All reactions were carried out under argon in flame-dried
glassware using standard Schlenk-line and glove box techni-
ques unless indicated otherwise. Tetrahydrofuran (THF) and
diethyl ether were freshly distilled from sodium/benzophe-
none under argon. Other solvents used for reactions were
purified according to standard procedures. Thin layer chro-
matography (TLC) was performed on Merck precoated silica
gel F254 on aluminium foil. Visualisation was accomplished
with UV light and/or phosphomolybdic acid solution followed
by heating. Flash chromatography was performed using Merck
flash silica gel 60 (40–63 mm). Melting points were measured
with a heating plate H600 and are uncorrected. UV spectra
were recorded on a Perkin–Elmer Lambda 25 UV/VIS spectro-
meter. IR spectra were obtained on a Thermo Nicolet Avatar
360 FT-IR spectrometer and were measured using the ATR
method. NMR spectra were obtained on a Bruker Advance DRX
500 using CDCl3 as solvent. 1H and 13C NMR shifts are
reported in ppm relative to the solvent shift of residual
chloroform: d = 7.26 (1H), d = 77.16 (13C).24 Mass spectra and
HRMS measurements were performed on a Finnigan MAT-95;
ionisation potential: 70 eV. GC-MS spectra were obtained at an
ionisation potential of 70 eV on HP 5890/5891 series GC/MSD.
Elemental analyses were obtained on a Euro Vector CHNS-O
elemental analyser. The X-ray analysis was performed on a
STOE STADI-4 diffractometer using Mo-Ka radiation. The
programmes ORTEP-3 and POV-Ray were used for the
graphical representation of the crystal structure.
6a: yield: 190 mg (10%); light yellow oil. IR (ATR): n = 3069,
3020, 2952, 2896, 2794, 1927, 1603, 1533, 1491, 1453, 1428,
1367, 1317, 1292, 1244, 1194, 1125, 1076, 1041, 1007, 991, 941,
836, 808, 771, 741, 719, 691, 666, 640, 619 cm21. 1H NMR (500
MHz, CDCl3): d = 0.11 (s, 9 H), 2.08 (br s, 1 H), 2.74 (dt, J = 16.2,
5.0 Hz, 1 H), 2.87–2.93 (m, 1 H), 3.00–3.05 (m, 1 H), 3.27 (dt, J =
12.1, 5.4 Hz, 1 H), 4.40 (t, J = 1.5 Hz, 2 H), 4.75 (br s, 1 H), 7.07–
7.15 (m, 4 H). 13C NMR and DEPT (125 MHz, CDCl3): d = –0.49
(3 CH3), 29.65 (CH2), 41.61 (CH2), 59.53 (CH), 69.58 (CH2),
99.56 (C), 125.29 (CH), 126.06 (CH), 127.60 (CH), 128.86 (CH),
135.02 (C), 138.26 (C), 211.18 (C). MS (80 uC): m/z (%) = 244 (6,
[M + 1]+), 242 (4), 228 (9), 133 (36), 132 (100), 130 (11), 117 (15),
105 (10), 73 (10). HRMS: m/z calcd for C15H21NSi: 243.1443,
found: 243.1412.
1-(But-2-ynyl)-1,2,3,4-tetrahydroisoquinoline (5b) and 1-(1-
methylpropa-1,2-dienyl)-1,2,3,4-tetrahydroisoquinoline (6b)
Starting material: 1.00 g (7.62 mmol) 3. Yield: 934 mg (66%)
(5b : 6b = 1 : 10); yellow oil. By very careful multiple column
chromatography, 5b and 6b can be separated from each other.
Compound 5b has the same Rf value as 3.
1
5b: H NMR (500 MHz, CDCl3): d = 1.82 (t, J = 2.5 Hz, 3 H),
2.06 (br s, 1 H), 2.53–2.59 (m, 1 H), 2.67–2.72 (m, 1 H), 2.80–
2.88 (m, 2 H), 3.00–3.05 (m, 1 H), 3.24 (quint, J = 5.9 Hz, 1 H),
4.10 (dd, J = 9.5, 3.7 Hz, 1 H), 7.08–7.17 (m, 4 H). 13C NMR and
DEPT (125 MHz, CDCl3): d = 3.78 (CH3), 26.77 (CH2), 30.01
(CH2), 40.62 (CH2), 55.15 (CH), 76.62 (C), 78.03 (C), 125.94
(CH), 126.27 (CH), 126.47 (CH), 129.39 (CH), 135.45 (C), 137.84
(C). MS (25 uC): m/z (%) = 185 (1, [M]+), 184 (3), 133 (12), 132
(100), 131 (7), 130 (12), 117 (10). HRMS: m/z calcd for C13H15N:
185.1204, found: 185.1201.
General procedure for the synthesis of 5a–c, 6a–c, 12 and 13
BF3?OEt2 (1.0 equiv.) was added dropwise at 223 uC to a
solution of 3,4-dihydroisoquinoline 3 or 11 (1.0 equiv.) in dry
THF and the mixture was stirred for 0.5 h. A solution of the
substituted propargyl Grignard reagent 4 (3.0 equiv.) in dry
Et2O was added dropwise to this suspension. After stirring for
15 h at 223 uC, the reaction mixture was poured into a
saturated aqueous solution of NH4Cl (100 mL) and extracted
with EtOAc. The combined organic layers were washed with
H2O and dried over Na2SO4. Evaporation of the solvent in
vacuo and flash chromatography of the residue on silica gel
(hexane/EtOAc 1 : 1) afforded the homopropargylamines 5a–c
and 12, and the allenes 6a–c and 13.
6b: UV (MeOH): l = 257, 265, 272, 596, 309 nm. IR (ATR): n =
3321, 3057, 3019, 2922, 2830, 2707, 1957, 1604, 1492, 1453,
1428, 1366, 1292, 1209, 1124, 1057, 1037, 990, 940, 846, 796,
1
742, 642 cm21. H NMR (500 MHz, CDCl3): d = 1.65 (t, J = 3.1
Hz, 3 H), 1.82 (br s, 1 H), 2.72 (dt, J = 16.2, 4.5 Hz, 1 H), 2.87–
2.93 (m, 1 H), 3.02–3.07 (m, 1 H), 3.27 (dt, J = 11.9, 5.1, 1 H),
4.60 (s, 1 H), 4.61–4.66 (m, 2 H), 7.08–7.10 (m, 1 H), 7.12–7.15
(m, 3 H). 13C NMR and DEPT (125 MHz, CDCl3): d = 14.80
(CH3), 29.76 (CH2), 42.18 (CH2), 61.06 (CH), 74.45 (CH2),
100.98 (C), 125.68 (CH), 126.41 (CH), 127.31 (CH), 129.12 (CH),
135.80 (C), 136.73 (C), 208.38 (C). MS (25 uC): m/z (%) = 186 (35,
[M + 1]+), 185 (8, [M]+), 184 (17), 170 (12), 169 (17), 141 (12), 133
(80), 132 (100), 131 (16), 130 (48), 129 (9), 128 (8), 117 (58), 115
(23), 105 (34), 103 (14), 77 (14). HRMS: m/z calcd for C13H15N:
185.1204, found: 185.1198.
1-(3-Trimethylsilylprop-2-ynyl)-1,2,3,4-tetrahydroisoquinoline
(5a) and 1-(1-trimethylsilylpropa-1,2-dienyl)-1,2,3,4-
tetrahydroisoquinoline (6a)
Starting material: 1.00 g (7.62 mmol) 3. 5a: yield: 1.48 g
(80%); orange oil. UV (MeOH): l = 265, 272, 349 nm. IR (ATR):
n = 3063, 3020, 2957, 2925, 2808, 2171, 1493, 1454, 1426, 1377,
1315, 1249, 1125, 1038, 1007, 959, 838, 758, 738, 718, 699, 649,
1-(3-Phenylprop-2-ynyl)-1,2,3,4-tetrahydroisoquinoline (5c)
and 1-(1-phenylpropa-1,2-dienyl)-1,2,3,4-
tetrahydroisoquinoline (6c)
1
629, 600 cm21. H NMR (500 MHz, CDCl3): d = 0.16 (s, 9 H),
2.28 (br s, 1 H), 2.64 (dd, J = 16.9, 9.4 Hz, 1 H), 2.77 (dd, J =
16.9, 4.0 Hz, 1 H), 2.81–2.84 (m, 2 H), 3.03 (quint, J = 6.0 Hz, 1
H), 3.23 (quint, J = 5.9 Hz, 1 H), 4.16 (dd, J = 9.3, 3.9 Hz, 1 H),
7.09–7.16 (m, 4 H). 13C NMR and DEPT (125 MHz, CDCl3): d =
0.21 (3 CH3), 28.10 (CH2), 30.02 (CH2), 40.52 (CH2), 54.84 (CH),
Starting material: 1.00 g (7.62 mmol) 3. Yield: 360 mg (19%)
(5c : 6c = 1 : 1.5); yellow oil. By very careful multiple column
chromatography, compound 6c could be separated as a light
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yellow oil. However, 5c could not be obtained as a pure
compound.
(25 mL). The aqueous layer was extracted with CH2Cl2 (4 6 50
mL) and dried over Na2SO4. Removal of the solvent and
purification of the residue by flash chromatography on silica
gel (hexane/EtOAc 1 : 2) afforded 5d, yield: 333 mg (87%); light
orange oil. UV (MeOH): l = 257, 264, 272, 348. IR (ATR): n =
3290, 3059, 3019, 2914, 2833, 2724, 2114, 1951, 1669, 1620,
1559, 1492, 1454, 1426, 1376, 1315, 1124, 1061, 1037, 964, 815,
739, 718, 628 cm21. 1H NMR (500 MHz, CDCl3): d = 2.07 (t, J =
2.6 Hz, 1 H), 2.22 (br s, 1 H), 2.59 (ddd, J = 16.8, 9.2, 2.6 Hz, 1
H), 2.72 (ddd, J = 16.8, 3.9, 2.7 Hz, 1 H), 2.78 (dt, J = 16.3, 5.7
Hz, 1 H), 2.84 (dt, J = 16.3, 6.1 Hz, 1 H), 2.99–3.04 (m, 1 H),
3.19–3.24 (m, 1 H), 4.15 (dd, J = 9.1, 3.9 Hz, 1 H), 7.07–7.18 (m,
4 H). 13C NMR and DEPT (125 MHz, CDCl3): d = 26.17 (CH2),
29.66 (CH2), 40.36 (CH2), 54.48 (CH), 70.37 (CH), 81.82 (C),
125.67 (CH), 125.88 (CH), 126.28 (CH), 129.15 (CH), 135.17 (C),
137.23 (C). MS (25 uC): m/z (%) = 171 (2, [M]+), 133 (23), 132
(100), 130 (16), 117 (20), 115 (10), 105 (14), 103 (7), 77 (7).
HRMS: m/z calcd for C12H13N: 171.1048, found: 171.1037.
6c: UV (MeOH): l = 249 nm. IR (ATR): n = 3055, 3021, 2916,
2832, 1936, 1596, 1492, 1449, 1426, 1290, 1180, 1156, 1113,
1
1060, 1032, 912, 847, 738, 692, 669, 612 cm21. H NMR (500
MHz, CDCl3): d = 2.50 (br s, 1 H), 2.87–2.90 (m, 2 H), 3.08
(quint, J = 6.0 Hz, 1 H), 3.31 (quint, J = 6.1 Hz, 1 H), 4.93 (dd, J =
12.1, 1.2 Hz, 1 H), 4.97 (d, J = 12.0 Hz, 1 H) 5.23 (s, 1 H), 7.11–
7.17 (m, 4 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.33 (t, J = 7.7 Hz, 2 H),
7.48 (d, J = 7.6 Hz, 2 H). 13C NMR and DEPT (125 MHz, CDCl3):
d = 29.11 (CH2), 40.81 (CH2), 57.45 (CH), 79.23 (CH2), 108.22
(C), 125.83 (CH), 126.71 (CH), 127.07 (2 CH), 127.23 (CH),
127.92 (CH), 128.81 (2 CH), 129.09 (CH), 134.86 (C), 135.01 (C),
136.37 (C), 210.40 (C). MS (25 uC): m/z (%) = 247 (8, [M]+), 246
(14), 133 (9), 132 (100), 130 (6), 117 (7), 115 (6). HRMS: m/z
calcd for C18H17N: 247.1361, found: 247.1364.
6,7-Dimethoxy-1-(3-trimethylsilylprop-2-ynyl)-1,2,3,4-
tetrahydroisoquinoline (12) and 6,7-dimethoxy-1-(1-
trimethylsilylpropa-2-dienyl)-1,2,3,4-tetrahydroisoquinoline
(13)
Silver(I)-promoted oxidative cyclisation: procedure A
Silver(I) acetate (1.1 equiv.) was added to a solution of the
tetrahydroisoquinolines 5a, 5b/6b, 5c/6c, 5d or 12 (1.0 equiv.)
in CH2Cl2 at room temperature and the reaction mixture was
stirred in the absence of light for 14 h. Filtration over a short
pad of neutral alumina (hexane/EtOAc 1 : 1) and removal of
the solvent provided the pyrroles 7a, 7b/9b, 7c/9c and 14.
Starting material: 1.50 g (7.84 mmol) 11. 12: yield: 1.44 g
(61%); yellow crystals, m.p. 59–69 uC. UV (MeOH): l = 206, 232,
285 nm. IR (ATR): n = 2998, 2955, 2905, 2832, 2170, 1610, 1515,
1464, 1376, 1354, 1326, 1301, 1250, 1224, 1113, 1036, 982, 841,
1
760, 700, 643 cm21. H NMR (500 MHz, CDCl3): d = 0.16 (s, 9
H), 1.79 (br s, 1 H), 2.63 (dd, J = 16.9, 8.9 Hz, 1 H), 2.70–2.74
(m, 3 H), 3.01 (quint, J = 5.9 Hz, 1 H), 3.20 (quint, J = 5.9 Hz, 1
H), 3.84 (s, 3 H), 3.85 (s, 3 H), 4.09–4.11 (m, 1 H), 6.58 (s, 1 H),
6.66 (s, 1 H). 13C NMR and DEPT (125 MHz, CDCl3): d = 0.27 (3
CH3), 28.34 (CH2), 29.56 (CH2), 40.58 (CH2), 54.70 (CH), 55.99
(CH3), 56.12 (CH3), 87.19 (C), 104.80 (C), 109.42 (CH), 111.81
(CH), 127.53 (C), 129.55 (C), 147.32 (C), 147.77 (C). MS (25 uC):
m/z (%) = 304 (5, [M + 1]+), 288 (7), 193 (68), 192 (100), 190 (6),
177 (14), 176 (39), 148 (18), 147 (10), 131 (9), 118 (6), 73 (7).
HRMS: m/z calcd for C17H25NO2Si: 303.1655, found: 303.1653.
Elemental analysis calcd for C17H25NO2Si: C 67.28, H 8.30, N
4.62, found C 67.07, H 8.31, N 4.79.
Silver(I)-promoted oxidative cyclisation: procedure B
Silver(I) acetate (1.1 equiv.) was added to a solution of the
substituted tetrahydroisoquinolines 6a or 13 (1.0 equiv.) in
acetone and the reaction mixture was heated at reflux in the
absence of light for 14 h. Filtration over a short pad of neutral
alumina (hexane/EtOAc 1 : 1) and removal of the solvent
provided the pyrroles 7a and 14.
5,6-Dihydropyrrolo[2,1-a]isoquinoline (7a)
PROCEDURE A: 80 mg (0.33 mmol) 5a; yield: 40 mg (72%) 7a.
PROCEDURE B: 103 mg (0.423 mmol) 6a; yield: 40 mg (56%) 7a.
7a: light yellow oil. UV (MeOH): l = 293, 303 (sh) nm. IR
(ATR): n = 3098, 3044, 2927, 2879, 1689, 1606, 1577, 1550, 1494,
1460, 1427, 1413, 1334, 1316, 1275, 1245, 1230, 1200, 1167,
1102, 1070, 1053, 1045, 1029, 997, 970, 939, 842, 782, 751, 732,
13: yield: 55 mg (2%); orange oil. UV (MeOH): l = 209, 227,
282, 328 nm. IR (ATR): n = 2999, 2951, 2905, 2831, 2171, 1927,
1609, 1558, 1514, 1464, 1355, 1325, 1249, 1222, 1119, 1031,
1
840, 761, 698, 643 cm21. H NMR (500 MHz, CDCl3): d = 0.07
1
706, 689, 673, 652, 605 cm21. H NMR (500 MHz, CDCl3): d =
(s, 6 H), 0.16 (s, 3 H), 1.60 (br s, 1 H), 2.60 (dt, J = 16.0, 4.9 Hz, 1
H), 2.75–2.81 (m, 1 H), 2.94–2.99 (m, 1 H), 3.21 (dt, J = 12.2, 5.3
Hz, 1 H), 3.82 (s, 3 H), 3.85 (s, 3 H), 4.36 (d, J = 1.1 Hz, 2 H),
4.63 (br s, 1 H), 6.55 (s, 1 H), 6.58 (s, 1 H). 13C NMR and DEPT
(125 MHz, CDCl3): d = 20.39 (2 CH3), 0.17 (CH3), 26.93 (CH2),
41.90 (CH2), 55.89 (CH3), 56.03 (CH3), 59.33 (CH), 69.74 (CH2),
99.81 (C), 110.76 (CH), 111.40 (CH), 127.28 (C), 130.43 (C),
146.80 (C), 147.43 (C), 211.08 (C). MS (25 uC): m/z (%) = 304 (7,
[M + 1]+), 288 (9), 194 (8), 193 (69), 192 (100), 177 (17), 176 (41),
148 (21), 147 (12), 131 (10), 73 (8). HRMS: m/z calcd for
C17H26NO2Si [M + 1]+: 304.1727, found: 304.1724.
3.09 (t, J = 6.6 Hz, 2 H), 4.10 (t, J = 6.6 Hz, 2 H), 6.25 (dd, J = 3.5,
2.7 Hz, 1 H), 6.54 (dd, J = 3.5, 1.5 Hz, 1 H), 6.70–6.71 (m, 1 H),
7.12 (dt, J = 7.4, 1.1 Hz, 1 H), 7.19 (dd, J = 7.5, 0.4 Hz, 1 H),
7.23–7.26 (m, 1 H), 7.55 (dd, J = 7.6, 0.4 Hz, 1 H). 13C NMR and
DEPT (125 MHz, CDCl3): d = 29.61 (CH2), 44.24 (CH2), 103.75
(CH), 108.69 (CH), 120.95 (CH), 122.53 (CH), 125.65 (CH),
127.23 (CH), 128.06 (CH), 129.72 (C), 129.95 (C), 130.43 (C). MS
(25 uC): m/z (%) = 169 (100, [M]+), 168 (67), 167 (25), 166 (5), 154
(5), 141 (5), 84 (9). HRMS: m/z calcd for C12H11N: 169.0891,
found: 169.0888.
3-Methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (7b)
1-(Prop-2-ynyl)-1,2,3,4-tetrahydroisoquinoline (5d)
A 1 M solution of TBAF in THF (2.25 mL, 2.25 mmol) was
PROCEDURE A: 80 mg (0.43 mmol) 5b (without any traces of
6b, but with a small contamination of 3); yield: 30 mg (38%) 7b
(with traces of 9b). 7b: orange crystals, m.p. 67 uC. 1H NMR
(500 MHz, CDCl3): d = 2.28 (s, 3 H), 3.06 (t, J = 6.0 Hz, 2 H), 3.95
added dropwise at room temperature to
a solution of
compound 5a (547 mg, 2.25 mmol) in THF (15 mL). After
stirring for 3 h, the reaction mixture was quenched with brine
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(t, J = 6.6 Hz, 2 H), 5.96 (d, J = 3.4 Hz, 1 H), 6.45 (d, J = 3.6 Hz, 1
H), 7.07 (td, J = 7.4, 1.1 Hz, 1 H), 7.17 (d, J = 7.3 Hz, 1 H), 7.21 (t,
J = 7.5 Hz, 1 H), 7.49 (d, J = 7.7 Hz, 1 H). 13C NMR and DEPT
(125 MHz, CDCl3): d = 12.05 (CH3), 29.44 (CH2), 40.71 (CH2),
102.96 (CH), 107.36 (CH), 122.19 (CH), 125.19 (CH), 127.18
(CH), 127.91 (CH), 128.92 (C), 129.26 (C), 129.80 (C), 130.13
(C). MS (25 uC): m/z (%) = 183 (100, [M]+), 182 (97), 181 (13), 180
(29), 167 (55). HRMS: m/z calcd for C13H13N: 183.1048, found:
183.1043.
Hz, 1 H), 6.65 (br s, 1 H), 6.70 (s, 1 H), 7.02 (s, 1 H). 13C NMR
and DEPT (125 MHz, CDCl3): d = 29.21 (CH2), 44.41 (CH2),
56.16 (CH3), 56.17 (CH3), 102.38 (CH), 106.07 (CH), 108.46
(CH), 111.45 (CH), 120.52 (CH), 122.73 (C), 122.91 (C), 130.07
(C), 147.36 (C), 148.38 (C). MS (25 uC): m/z (%) = 229 (100, [M]+),
214 (46), 186 (19), 185 (6), 171 (7). HRMS: m/z calcd for
C
14H15NO2: 229.1103, found: 229.1105. Elemental analysis
calcd for C14H15NO2: C 73.34, H 6.59, N 6.11, found C 73.37, H
6.88, N 6.05.
Crystallographic data for 14. C14H15NO2, crystal size: 0.25 6
1-Methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (9b)
0.24 6 0.04 mm3, M = 229.27 g mol21, triclinic, space group P1
¯
PROCEDURE A (WITH ACETONE INSTEAD OF CH2CL2 AS SOLVENT): 144
mg (0.777 mmol) 6b (without any traces of 5b); yield: 49 mg
(34%) mixture of 7b and 9b (1 : 6). 9b: light yellow oil. 1H NMR
(500 MHz, CDCl3): d = 2.43 (s, 3 H), 3.04 (t, J = 6.5 Hz, 2 H), 4.05
(t, J = 6.5 Hz, 2 H), 6.07 (d, J = 2.5 Hz, 1 H), 6.60 (d, J = 2.5 Hz, 1
H), 7.11 (td, J = 7.4, 1.1 Hz, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.27–
7.30 (m, 1 H), 7.61 (d, J = 7.8 Hz, 1 H). 13C NMR and DEPT (125
MHz, CDCl3): d = 14.14 (CH3), 30.52 (CH2), 44.57 (CH2), 110.86
(CH), 116.24 (C), 119.32 (CH), 123.26 (CH), 124.87 (CH), 125.32
(C), 127.08 (CH), 128.11 (CH), 130.86 (C), 131.53 (C). MS (25
uC): m/z (%) = 183 (100, [M]+), 182 (82), 180 (12), 167 (20), 147
(22), 146 (13), 118 (16). HRMS: m/z calcd for C13H13N:
183.1048, found: 183.1045.
, l = 0.71073 Å, a = 7.082(1), b = 8.632(1), c = 10.345(1) Å, a =
65.370(10), b = 88.98(1), c = 83.89(1)u, V = 571.36(12) Å3, Z = 2,
rc = 1.333 g cm23, m = 0.089 mm21, T = 198(2)K, h range = 3.56–
25.40u, reflections collected: 9798, independent: 2103 (Rint
=
0.0443), 156 parameters. The structure was solved by direct
methods and refined by full-matrix least-squares on F2; final R
indices [I . 2s(I)]: R1 = 0.0428, wR2 = 0.0925; maximal residual
electron density: 0.160 e Å23. CCDC 873921.
General procedure for the chemoselective hydrogenation of
the pyrrole ring
7a or 14 (1 equiv.) was added to a suspension of 5% rhodium
on activated carbon (25% by wt) in methanol and glacial acetic
acid (1 : 1). The mixture was vigorously stirred under a
hydrogen atmosphere (800–900 Torr) at room temperature
until no further hydrogen uptake was detected (8 days). The
reaction mixture was filtered over a short path of Celite1
(methanol). After removal of the solvent, the residue was
neutralised with 2 N sodium hydroxide solution and extracted
four times with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated in vacuo to afford the
hexahydropyrroloisoquinolines 8 and 1.
3-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (7c) and
1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (9c)
PROCEDURE A: 336 mg (1.36 mmol) mixture of 5c and 6c
(1 : 1.5); yield: 156 mg (47%) mixture of 7c and 9c (1 : 1.5);
orange oil.
1-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (9c)
PROCEDURE A: 90 mg (0.36 mmol) 6c (without any traces of
5c); yield: 32 mg (36%) 9c. 9c: orange oil. UV (MeOH): l = 241,
256, 309 nm. IR (ATR): n = 3053, 3029, 2952, 2923, 2879, 1736,
1697, 1603, 1498, 1471, 1458, 1445, 1397, 1329, 1263, 1213,
1,2,3,5,6,10b-Hexahydropyrrolo[2,1-a]isoquinoline (8)
STARTING MATERIAL: 86 mg (0.51 mmol) 7a. 8: yield: 80 mg
(91%); light yellow oil. UV (MeOH): l = 265, 272, 291, 309 (sh)
nm. IR (ATR): n = 2922, 2872, 2783, 1578, 1493, 1452, 1377,
1351, 1325, 1285, 1255, 1218, 1182, 1162, 1136, 1116, 1082,
1
1188, 1072, 1015, 942, 911, 761, 730, 699, 650, 623 cm21. H
NMR (500 MHz, CDCl3): d = 3.10 (t, J = 6.4 Hz, 2 H), 4.07 (t, J =
6.4 Hz, 2 H), 6.24 (d, J = 2.6 Hz, 1 H), 6.73 (d, J = 2.6 Hz, 1 H),
7.00 (td, J = 7.6, 1.3 Hz, 1 H), 7.06 (td, J = 7.4, 1.3 Hz, 1 H), 7.19
(d, J = 7.3 Hz, 1 H), 7.26–7.29 (m, 1 H), 7.33–7.38 (m, 3 H), 7.49
(dd, J = 8.1, 1.2 Hz, 2 H). 13C NMR and DEPT (125 MHz,
CDCl3): d = 30.38 (CH2), 44.83 (CH2), 110.63 (CH), 120.42 (CH),
122.64 (C), 124.14 (CH), 124.97 (C), 125.72 (CH), 126.24 (CH),
126.75 (CH), 128.08 (CH), 128.54 (2 CH), 129.14 (2 CH), 129.86
(C), 132.04 (C), 137.82 (C). MS (25 uC): m/z (%) = 245 (100, [M]+),
244 (81), 243 (34), 242 (20), 241 (18), 194 (12). HRMS: m/z calcd
for C18H15N: 245.1204, found: 245.1209.
1
1040, 1013, 932, 913, 876, 740, 650 cm21. H NMR (500 MHz,
CDCl3): d = 1.72–1.79 (m, 1 H), 1.83–1.99 (m, 2 H), 2.35–2.41
(m, 1 H), 2.63 (q, J = 8.6 Hz, 1 H), 2.71 (ddd, J = 11.1, 10.1, 4.8
Hz, 1 H), 2.85 (dt, J = 16.6, 4.0 Hz, 1 H), 3.04–3.13 (m, 2 H),
3.15–3.21 (m, 1 H), 3.54 (t, J = 8.3 Hz, 1 H), 7.07–7.17 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 22.38 (CH2), 28.47 (CH2), 30.56
(CH2), 48.40 (CH2), 53.41 (CH2), 63.20 (CH), 125.85 (CH),
126.00 (CH), 126.21 (CH), 128.57 (CH), 134.17 (C), 138.67 (C).
MS (25 uC): m/z (%) = 173 (46, [M]+), 172 (100), 170 (11), 145
(36), 117 (18). HRMS: m/z calcd for C12H15N: 173.1204, found:
173.1206.
8,9-Dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline (14)
PROCEDURE A: 140 mg (0.461 mmol) 12; yield: 61 mg (58%) 14.
PROCEDURE B (with a reaction time of only 6 h): 40 mg (0.13
mmol) 13; yield: 13 mg (43%) 14.
14: light yellow crystals, m.p. 110–112 uC. UV (MeOH): l =
293, 308 (sh), 314 nm. IR (ATR): n = 2935, 2835, 1611, 1553,
1506, 1464, 1441, 1393, 1333, 1305, 1266, 1243, 1226, 1210,
1166, 1131, 1073, 1050, 1015, 859, 791, 711 cm21. 1H NMR (500
MHz, CDCl3): d = 3.00 (t, J = 6.6 Hz, 2 H), 3.89 (s, 3 H), 3.92 (s, 3
H), 4.06 (t, J = 6.6 Hz, 2 H), 6.20 (br s, 1 H), 6.39 (br d, J = 2.3
( )-Crispine A (1)
STARTING MATERIAL: 90 mg (0.39 mmol) 14. 1: yield: 60 mg
(66%); colourless crystals, m.p. 76–78 uC. UV (MeOH): l = 232,
282, 286, 291 (sh) nm. IR (ATR): n = 2921, 2835, 2801, 1607,
1517, 1466, 1409, 1376, 1359, 1323, 1312, 1290, 1250, 1228,
1211, 1198, 1159, 1135, 1111, 1086, 1012, 962, 934, 913, 899,
871, 850, 811, 762, 721, 696 cm21. 1H NMR (500 MHz, CDCl3):
d = 1.69–1.76 (m, 1 H), 1.82–1.98 (m, 2 H), 2.29–2.35 (m, 1 H),
1094 | RSC Adv., 2013, 3, 1089–1096
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´
¨
¨
76, 5936; (w) E. Forro, L. Schonstein and F. Fu¨lop,
Tetrahedron: Asymmetry, 2011, 22, 1255; (x) N. Kawai,
M. Matsuda and J. Uenishi, Tetrahedron, 2011, 67, 8648.
2.56 (br q, J = 8.5 Hz, 1 H), 2.64 (td, J = 10.8, 4.7 Hz, 1 H), 2.73
(br dt, J = 16.4, 3.5 Hz, 1 H), 2.99–3.04 (m, 1 H), 3.08 (td, J = 8.7,
3.8 Hz, 1 H), 3.18 (ddd, J = 11.3, 6.2, 2.9 Hz, 1 H), 3.42 (br t, J =
7.9 Hz, 1 H), 3.84 (s, 3 H), 3.85 (s, 3 H), 6.57 (s, 1 H), 6.61 (s, 1
H). 13C NMR and DEPT (125 MHz, CDCl3): d = 22.37 (CH2),
28.19 (CH2), 30.63 (CH2), 48.51 (CH2), 53.30 (CH2), 56.03 (CH3),
56.14 (CH3), 63.10 (CH), 108.97 (CH), 111.46 (CH), 126.36 (C),
131.10 (C), 147.35 (C), 147.47 (C). MS (25 uC): m/z (%) = 233 (63,
[M]+), 232 (100), 218 (6), 216 (7), 205 (49), 190 (28), 177 (5).
HRMS: m/z calcd for C14H19NO2: 233.1416, found: 233.1391.
.
¨
¨
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for financial
support (KN 240/16-1).
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