Pictet-Spengler/palladium catalyzed allenylation and carbonylation processes

Article abstract of DOI:10.1016/S0040-4020(00)00628-1

The tactical combination of the Pictet-Spengler reaction with Pd catalyzed reactions with allene and with carbon monoxide provides rapid access to a range of tetrahydro-β-carboline and tetrahydroisoquinoline derivatives via intramolecular trapping of inte

Full text of DOI:10.1016/S0040-4020(00)00628-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6585±6594
Pictet±Spengler/Palladium Catalyzed Allenylation and
Carbonylation Processes
b
b
a
Ronald Grigg,a, William S. MacLachlan, David T. MacPherson, Visuvanathar Sridharan,
*
Selvaratnam Suganthan,a Mark Thornton-Petta and Jin Zhanga
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
bSmithKline Beecham, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
Received 11 May 2000; revised 21 June 2000; accepted 6 July 2000
AbstractÐThe tactical combination of the Pictet±Spengler reaction with Pd catalyzed reactions with allene and with carbon monoxide
provides rapid access to a range of tetrahydro-b-carboline and tetrahydroisoquinoline derivatives via intramolecular trapping of intermediate
p-allyl± and acyl±palladium(II) complexes by the indolic or secondary amino moieties generating fused azepine and d-lactam derivatives.
Chiral tryptophan examples are also described. q 2000 Elsevier Science Ltd. All rights reserved.
We have previously reported1 the combination of cascade
imine!azomethine ylide!cycloaddition reactions with the
Pictet±Spengler2 reaction. This tactical combination
provides rapid access to complex heterocycles with good
regio- and stereo-selectivity. In this paper we report sequen-
tial Pictet±Spengler/palladium catalyzed allenylation and
carbonylation sequences which allow rapid access to
novel and complex heterocycles.
Pictet±Spengler cyclization of imine (1a,b) proceeded
smoothly in the presence of catalytic amount of p-toluene-
sulphonic acid in boiling toluene to give 2a and 2b/2c in
excellent yield (81% and 88%, respectively).3 In the case of
1b, the product comprised a 1:1 trans/cis mixture of 2b and
2c. The stereochemistries of 2b and 2c were established by
n.O.e studies (see Experimental). Partial racemization
(,50%) occurred during this reaction.4
Pictet±Spengler products 2a±c undergo palladium cata-
lyzed allene insertion (allene 1 atm, toluene, 1108C, 16 h)
to give 3a±c in 77±92% yield (Scheme 1).5 The catalyst
system comprised 10 mol% Pd(OAc)2, 20 mol% PPh3,
Et4NCl (1 mol equiv.) and K2CO3 (2 mol equiv.). The alter-
native product 4 arising from capture of the intermediate
p-allyl species by the indole nitrogen atom was not
observed.
The Pictet±Spengler products 2a±c undergo palladium
catalyzed carbonylation (CO 1 atm, toluene, 40 or 1108C,
16 h) to give 5a±c in 67±93% yield. In this case catalyst
system comprised 10 mol% Pd(OAc)2, 20 mol% PPh3 and
Et3N (1.2 mol equiv.) (Scheme 2).6
The Pictet±Spengler cyclization of imines 6a,b also
proceeded smoothly to afford substituted tetrahydroiso-
quinoline derivatives 7a±c in high yield with 6b giving a
3:2 trans/cis mixture (61%) of 7b and 7c. The stereo-
chemistries of 7b and 7c were established by n.O.e. studies
(see Experimental).
Keywords: Pictet±Spengler; Pd catalysis; allenylation; carbonylation; tetra-
hydro-b carbolines; tetrahydroisoquinolines.
* Corresponding author. Tel./fax: 144-113-233-6501;
e-mail: r.grigg@chem.leeds.ac.uk
The Pictet±Spengler products 7a±c underwent palladium
catalyzed allenylation and carbonylation processes
under essentially similar conditions to the foregoing
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00628-1

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R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
Scheme 1.
tetrahydro-b-carboline series to afford 8a±c and 9a,b in
good yield, apart from 7c which failed to undergo carbony-
lation under these conditions.
aldehyde afforded 12a±d in 74±85% yield with exclusive
formation of the trans diastereoisomers (n.O.e.).7 There
was no detectable racemization of 12a±d by H NMR in
1
the presence of the chiral shift reagent tris(3-hepta-
¯uoropropylhydroxymethylene-(1)camphorato)europium
(III).8
Finally we turned our attention to intercepting the p-allyl
palladium intermediate with the indole nitrogen atom. To
explore this process, amines 11a±d were prepared in
excellent yield by reduction of the corresponding imines
10a±d using NaB(OAc)3H (Scheme 3).
The palladium catalyzed reactions of enantiopure 12a±d
with allene (1 atm) under essentially similar conditions to
those described above gave 13a±d in good to excellent yield
(Scheme 4).
The Pictet±Spengler reaction of 11a±d with 2-iodobenz-
Scheme 2.

R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
6587
Scheme 3.
Scheme 4.
The stereochemistry of 13d was con®rmed by X-ray crystal-
lography (Fig. 1).
Experimental
Melting points were obtained on a Reichert hot-stage
apparatus and are uncorrected. Microanalyses were
obtained using a Carlo Erba MOD 1106 instrument. Mass
spectra were recorded on a V.G. Autospec using electron
impact (EI) operating at 70 ev and accurate molecular
weights were determined using per¯uorokerosene as
internal standard. Infrared spectra were recorded on a
Nicolet Avatar 360 FI-IR instrument. Optical rotations
were recorded on an AA100 Polarimeter. X-Ray analysis
was performed on a Stoe STADI 4-circle machine. Nuclear
magnetic resonance spectra were recorded at 300 MHz on a
General Electric QE300 or Bruker DPX 300 instrument, at
250 MHz on a Bruker AC 250 instrument, at 400 MHz on a
Bruker WP 400 instrument or at 500 MHz on a Bruker DRX
500 instrument. Deuterochloroform was used as the NMR
solvent with tetramethylsilane as the internal standard.
Chemical shifts are given in parts per million (d) down
®eld from tetramethylsilane and coupling constants are
given in Hz. Solvents were puri®ed according to standard
procedures.9 The term ether refers to diethyl ether and
petroleum ether refers to the fraction with boiling point
Figure 1. The X-ray crystal structure of 13d.

6588
R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
40±608C. Flash chromatography employed silica gel 60
(230±400 mesh).
under 1 atm of allene. On completion of the reaction (NMR
monitoring), the tube was cooled, vented, the solvent
removed in vacuo, DCM (100 ml) added and the mixture
washed with water(100 ml). The separated organic layer
was dried (MgSO4), concentrated in vacuo and the residue
puri®ed by ¯ash column chromatography.
A. General procedure for preparation of imines
A mixture of amine (11 mmol), aldehyde (10 mmol) and
anhydrous magnesium sulphate (2 g) in dry DCM (80 ml)
was stirred at room temperature for 16 h. On completion of
the reaction (NMR monitoring), the mixture was diluted
with DCM (100 ml), washed with water (2£100 ml), dried
(MgSO4) and concentrated in vacuo to give imine
which was used in the next step without further
puri®cation. N.B.: When the amine hydrochloride salt was
used, triethylamine (1.21 g, 12 mmol) was added to the
reaction mixture.
[2-(1H-Indol-3-yl)ethyl]-(2-iodo-benzylidene)-amine 1a.
Prepared by general procedure A from tryptamine (1.41 g,
8.8 mmol) and 2-iodobenzaldehyde (1.87 g, 8 mmol). Work
up afforded 1a (2.69 g, 90%) which crystallized from
ethanol as pale orange prisms. Mp 121±1238C. (Found: C,
54.35; H, 4.05; N, 7.35; I, 34.05. C17H15N2I requires: C,
54.55; H, 4.05; N, 7.05; I, 33.9%); d: 3.19 (t, 2H,
Jˆ7.2 Hz, ArCH2), 4.00 (dt, 2H, Jˆ1.3, 7.3 Hz, NCH2),
7.04±7.40 (m, 6H, ArH), 7.68 (d, 1H, Jˆ7.5 Hz, ArH),
7.83 (dd, 1H, Jˆ1.1, 7.9 Hz, ArH), 7.96 (dd, 2H, Jˆ1.7,
7.8 Hz, ArH and indole-NH) and 8.31 (s, 1H, NvCH);
m/z (%): 374 (M1, 9), 244 (4), 232 (14), 130 (100), 89 (9)
and 77 (13).
B. General procedure for reduction of imines to amines
A mixture of imine (8 mmol) and sodium triacetoxyboro-
hydride (2.37 g, 11.2 mmol) in 1,2-dichloroethane (40 ml)
was stirred at room temperature under N2 for 24 h. On
completion of the reaction (NMR monitoring), the mixture
was quenched with saturated aqueous NaHCO3 (100 ml)
and DCM (150 ml) was added. The separated aqueous
phase was extracted with ether (3£150 ml), the combined
organic phase dried (MgSO4), concentrated in vacuo and the
residue puri®ed by ¯ash column chromatography to afford
the product.
[3-(1H-Indol-3-yl)ethyl]-2-(2-iodo-benzylideneamino)-
propionic acid methyl ester 1b. Prepared by general proce-
dure A from tryptophan methyl ester hydrochloride (2.24 g,
8.8 mmol) and 2-iodobenzaldehyde (1.87 g, 8 mmol). Work
up afforded 1b (3.28 g, 95%) as a pale yellow gum. d: 3.26
(dd, 1H, Jˆ8.8, 14.5 Hz, ArCHH), 3.57 (dd, 1H, Jˆ4.9,
14.5 Hz, ArCHH), 3.78 (s, 3H, OCH3), 4.39 (dd, 1H,
Jˆ4.8, 8.8 Hz, NCHCO2Me), 6.96 (d, 1H, Jˆ2.4 Hz,
ArH), 7.04±7.20 (m, 3H, ArH), 7.31±7.67 (m, 2H, ArH),
7.75 (d, 1H, Jˆ1.1 Hz, ArH), 7.78 (d, 1H, Jˆ1.1 Hz, ArH),
7.98 (d, 1H, Jˆ1.7 Hz, ArH), 8.00 (s, 1H, NvCH) and 8.03
(br, 1H, NH); m/z (%): 432 (M1, 6), 232 (9), 130 (100) and
77 (6).
C. General procedure for Pictet±Spengler reactions
(1). A mixture of imine (8 mmol) and p-toluenesulphonic
acid monohydrate (0.152 g, 0.8 mmol) in toluene (80 ml)
was stirred and boiled under re¯ux for 6±8 h. On comple-
tion of the reaction (NMR monitoring), the solvent was
removed in vacuo and the residue puri®ed by ¯ash column
chromatography to afford the product.
1-(2-Iodo-phenyl)-2,3,4,9-tetrahydro-1H-b-carboline 2a.
Prepared by general procedure C(1) from imine 1a (2.99 g,
8 mmol) and p-toluenesulphonic acid monohydrate
(0.152 g, 0.8 mmol) over 8 h. Flash chromatography eluting
with 1:2 v/v ether±hexane afforded 2a (2.42 g, 81%) which
crystallized from ethyl acetate as pale yellow prisms. Mp
139±1418C. (Found: C, 54.85; H, 4.25; N, 7.2; I, 34.1.
C17H15N2I requires: C, 54.55; H, 4.05; N, 7.5; I, 33.9%);
d: 2.01 (br, 1H, NH), 2.81±2.86 (m, 2H, ArCH2), 3.06±3.19
(m, 2H, NCH2), 5.45 (s, 1H, ArCHN), 6.94±7.22 (m, 6H,
ArH), 7.53 (m, 1H, ArH) and 7.86±7.91 (m, 2H, ArH and
indole-NH); m/z (%): 374 (M1, 100), 345 (27), 245 (14),
218 (83), 171 (64), 123 (23) and 77 (7).
(2). A mixture of amine (6 mmol), 2-iodobenzaldehyde
(1.39 g, 6 mmol) and p-toluenesulphonic acid monohydrate
(0.114 g, 0.6 mmol) in toluene (80 ml) was stirred and
boiled under re¯ux with a Dean±Stark apparatus for 16 h.
The solvent was removed in vacuo and the residue puri®ed
by ¯ash column chromatography to afford the product.
D. General procedure for carbonylation
A mixture of Pictet±Spengler product (1 mmol), Pd(OAc)2
(0.022 g, 0.1 mmol), PPh3 (0.052 g, 0.2 mmol) and Et3N
(0.101 g, 1 mmol) in toluene (10 ml) was stirred and heated
at 40±1108C for 16 h under a carbon monoxide balloon. The
solvent was removed in vacuo, DCM (100 ml) added and
the mixture washed with water (100 ml). The separated
organic layer was dried (MgSO4), concentrated in vacuo
and the residue puri®ed by ¯ash column chromatography
to afford the product.
trans-1-(2-Iodo-phenyl)-2,3,4,9-tetrahydro-1H-b-carbo-
line-3-carboxylic acid methyl ester 2b and cis-1-(2-iodo-
phenyl)-2,3,4,9-tetrahydro-1H-b-carboline-3-carboxylic
acid methyl ester 2c. Prepared by general procedure C(1)
from imine 1b (4.32 g, 10 mmol) and p-toluenesulphonic
acid monohydrate (0.190 g, 1.0 mmol) over 6 h. The
product comprised a 1:1 mixture of 2b and 2c (1H NMR).
cis isomer 2c: Flash chromatography eluting with 3:1 v/v
chloroform/hexane afforded 2c (1.55 g, 37%) which crystal-
lized from ether±petroleum ether as colorless needles. Mp
149±1518C. (Found: C, 52.95; H, 3.85; N, 6.2; I, 29.15.
C19H17N2O2I requires: C, 52.8; H, 3.95; N, 6.5; I,
29.35%); d: 2.71 (br, 1H, NH), 3.02 (ddd, 1H, Jˆ2.5,
E. General procedure for allenylation
A mixture of Pictet±Spengler product (1 mmol), Pd(OAc)2
(0.022 g, 0.1 mmol), PPh3 (0.052 g, 0.2 mmol), Et4NCl
(0.166 g, 1 mmol) and K2CO3 (0.276 g, 2 mmol) in toluene
(10 ml) was stirred and heated at 1108C in a Schlenk tube

R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
6589
11.1, 15.0 Hz, ArCHH), 3.24 (ddd, 1H, Jˆ1.8, 4.1, 15.0 Hz,
ArCHH), 3.81 (s, 3H, OCH3), 4.00 (dd, 1H, Jˆ4.1, 11.1 Hz,
NCHCO2Me), 5.64 (s, 1H, ArCHN), 7.03 (dt, 1H, Jˆ1.8,
7.5 Hz, ArH), 7.10±7.16 (m, 2H, ArH), 7.21±7.33 (m, 3H,
ArH) 7.53±7.55 (m, 2H, ArH and indole-NH) and 7.90 (dd,
1H, Jˆ1.2, 8.0 Hz, ArH); m/z (%): 432 (M1, 100), 373 (36),
305 (6), 229 (16) and 169 (21); nmax: 3387, 1730, 1431 and
3.52 and 3.79 (2£d, 2£1H, Jˆ13.3 Hz, NCH2C), 5.06 and
5.41 (2£s, 2£1H, CvCH2), 5.61 (s, 1H, ArCHN) and 7.05±
7.82 (m, 8H, ArH); m/z (%): 286 (M1, 100), 257 (48), 242
(17), 230 (12), 217 (10), 143 (27), 128 (21), 115 (18) and 77
(6).
Compound 3b. Prepared by general procedure E from 2b
(0.432, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 16 h. Flash chromatography eluting
with 2:3 v/v ether±petroleum ether afforded 3b (0.318 g,
92%) which crystallized from ether as pale yellow prisms.
Mp 134±1368C. (Found: C, 76.65; H, 6.0; N, 7.9.
C22H20N2O2 requires: C, 76.7; H, 5.85; N, 8.15%); d:
3.25±3.29 (m, 2H, ArCH2), 3.56 and 3.82 (2£d, 2£1H,
Jˆ13.4 Hz, NCH2), 3.75 (s, 3H, OCH3), 4.10 (dd, 1H,
Jˆ2.8, 6.3 Hz, NCHCO2Me), 5.04 (s, 1H, CvCHH), 5.62
(s, 2H, CvCHH and ArCHN), 7.06±7.16 (m, 2H, ArH),
7.26±7.43 (m, 4H, ArH), 7.50 (d, 1H, Jˆ8.3 Hz, ArH)
and 7.74±7.77 (m, 2H, ArH and indole-NH); m/z (%): 344
735 cm21
.
(M1, 81), 330 (6), 285 (100), 271 (15) and 142 (37); nmax
3398, 1738, 1454 and 731 cm21
:
.
Compound 3c. Prepared by general procedure E from 2c
(0.432, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 16 h. Flash chromatography eluting
with 1:2 v/v ether±petroleum ether afforded 3c (0.266 g,
77%) as a pale yellow gum. (Found: C, 76.5; H, 5.75; N,
7.9. C22H20N2O2 requires: C, 76.7; H, 5.85; N, 8.15%); d:
3.09±3.29 (m, 2H, ArCH2), 3.25 and 3.64 (2£d, 2£1H,
Jˆ12.7 Hz, NCH2), 3.87 (s, 3H, OCH3), 4.25 (dd, 1H,
Jˆ5.4, 11.6 Hz, NCHCO2Me), 5.06 and 5.61 (2£s, 2£1H,
CvCH2), 5.49 (s, 1H, ArCHN), 7.07±7.16 (m, 2H, ArH),
7.25 (m, 1H, ArH), 7.29±7.41 (m, 3H, ArH), 7.52 (dd, 1H,
Jˆ2.0, 6.2 Hz, ArH) 7.66 (br, 1H, NH) and 7.75 (d, 1H,
Jˆ7.7 Hz, ArH); m/z (%): 344 (M1, 13), 285 (100), 271
(6), 257 (21) and 142 (11); nmax: 2922, 2358, 1696 and
trans isomer 2b: Continued ¯ash chromatography eluting
with 3:1 v/v chloroform/hexane afforded a mixture of 2b
and 2c (0.376 g, 9%) followed by pure 2b (1.77 g, 42%),
which crystallized from ether±petroleum ether as colorless
needles. Mp 149±1518C. (Found: C, 52.9; H, 3.8; N, 6.2; I,
29.25. C19H17N2O2I requires: C, 52.8; H, 3.95; N, 6.5; I,
29.35%); d: 2.84 (br, 1H, NH), 3.08 (ddd, 1H, Jˆ1.5, 7.7,
15.3 Hz, ArCHH), 3.25 (ddd, 1H, Jˆ1.1, 5.0, 15.3 Hz,
ArCHH), 3.71 (s, 3H, OCH3), 3.85 (dd, 1H, Jˆ5.0,
7.7 Hz, NCHCO2Me), 5.67 (s, 1H, ArCHN), 6.86 (dd, 1H
Jˆ1.7, 7.7 Hz, ArH), 6.97 (dt, 1H, Jˆ1.7, 7.7 Hz, ArH),
7.10±7.24 (m, 4H, ArH), 7.55 (dd, 1H, Jˆ1.5, 8.4 Hz,
ArH), 7.72 (s, 1H, indole-NH) and 7.89 (dd, 1H, Jˆ1.2,
7.9 Hz, ArH); m/z (%): 432 (M1, 100), 373 (41), 305 (14),
245 (26) and 170 (6); nmax: 3390, 1726, 1434 and 739 cm21
.
1454 cm21
.
Compound 5a. Prepared by general procedure D from 2a
(0.374 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol) and Et3N (0.101 g, 1 mmol) at 408C.
Flash chromatography eluting with 2:1 v/v ether±petroleum
ether afforded 5a (0.255 g, 93%) which crystallized from
ether±petroleum ether as colorless plates. Mp 212±2148C.
(Found: C, 78.7; H, 5.25; N, 10.0. C18H14N2O requires: C,
78.8; H, 5.15; N, 10.2%); d: 2.84±3.06 (m, 2H, ArCH2),
3.44 (m, 1H, NCHH), 4.88 (ddd, 1H, Jˆ1.5, 5.6, 13.3 Hz,
NCHH), 5.85 (s, 1H, ArCHN), 7.08±7.23 (m, 2H, ArH),
7.38 (m, 1H, ArH), 7.51 (t, 2H, Jˆ8.0 Hz, ArH), 7.63 (dt,
1H, Jˆ1.2, 7.5 Hz, ArH), 7.81 (dd, 1H, Jˆ0.8, 7.5 Hz,
ArH), 7.91 (dd, 1H, Jˆ0.9, 8.4 Hz, ArH) and 8.32 (br,
1H, NH); m/z(%): 274 (M1, 100), 245 (46), 217 (20), 189
Compound 3a. Prepared by general procedure E from 2a
(0.374 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 16 h. Flash chromatography eluting
with 2:1 v/v ether±hexane afforded 3a (0.270 g, 90%)
which crystallized from chloroform as pale yellow prisms.
Mp 203±2058C. (Found: C,83.6; H,6.5; N,9.9. C20H18N2
requires: C, 83.9; H, 6.3; N, 9.8%); d: 2.74 and 3.03
(2£m, 2£1H, ArCH2CH2), 3.39±3.44 (m, 2H, ArCH2CH2),
(6), 128 (10) and 109 (21); nmax: 3224, 1681 and 1313 cm21
.
trans-7-Oxo-6,7,11b,12-tetrahydro-5H-6a, 12-diaza-inde-
no[1,2-a]¯uorene-6-carboxylic acid methyl ester 5b.
Prepared by general procedure D from 2b (0.432 g,
1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3 (0.052 g,
0.2 mmol) and Et3N (0.101 g, 1 mmol) at 1108C. Flash chro-
matography eluting with 2:1 v/v ether±petroleum ether
afforded 5b (0.270 g, 81%) which crystallized from ether

6590
R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
as colorless rods. Mp 166±168 8C. (Found: C, 72.0; H, 4.9;
N, 8.2. C20H16N2O3 requires: C, 72.3; H, 4.85; N, 8.45%); d:
3.24 (ddd, 1H, Jˆ2.4, 7.5, 16.0 Hz, ArCHH), 3.46 (d, 1H,
Jˆ16.0 Hz, ArCHH), 3.72 (s, 3H, OCH3), 5.76 (d, 1H,
Jˆ7.0 Hz, NCHCO2Me), 6.23 (s, 1H, ArCHN), 7.09±7.21
(m, 2H, ArH), 7.36 (d, 1H, Jˆ7.9 Hz, ArH), 7.47±7.54 (m,
2H, ArH), 7.65 (dt, 1H, Jˆ1.1, 7.5 Hz, ArH), 7.81 (d, 1H,
Jˆ7.6 Hz, ArH), 7.93 (d, 1H, Jˆ7.5 Hz, ArH) and 8.31 (br,
1H, NH); m/z (%): 332 (M1, 69), 304 (7), 273 (36), 271
(100) and 245 (37); nmax: 3304, 1741, 1169, 1461 and
reduced to 5 ml, quenched with saturated aqueous Na2CO3
(100 ml) and extracted with ether (3£150 ml). The
combined organic phase was dried (MgSO4) and concen-
trated in vacuo. The residue was puri®ed by ¯ash column
chromatography eluting with 2:1 v/v ether±petroleum ether
to afford 7a (2.11 g, 89%) as a pale yellow gum. (Found: C,
51.55; H, 4.6; N, 3.45; I, 32.0. C17H18NO2I requires: C,
51.65; H, 4.6; N, 3.55; I, 32.1%); d: 2.07 (br, 1H, NH),
2.81±2.89 (m, 2H, ArCH2), 2.98±3.13 (m, 2H, NCH2),
3.67 and 3.88 (2£s, 2£3H, 2£OCH3), 5.37 (s, 1H,
ArCHN), 6.24 and 6.65 (2£s, 2£1H, 2£ArH), 6.92±6.98
(m, 2H, ArH) and 7.23 and 7.88 (2£m, 2£1H, ArH); m/z
(%): 395 (M1, 23), 380 (11), 364 (8), 268 (6), 239 (7), 192
(100), 165 (10) and 77 (6); nmax: 2934, 2829, 1517 and
1197 cm21
.
cis-7-Oxo-6,7,11b,12-tetrahydro-5H-6a,12-diaza-indeno-
[1,2-a]¯uorene-6-carboxylic acid methyl ester 5c.
Prepared by general procedure D from 2c (0.216 g,
0.5 mmol), Pd(OAc)2 (0.011 g, 0.05 mmol), PPh3 (0.026 g,
0.1 mmol) and Et3N (0.051 g, 0.5 mmol) at 110 8C. Flash
chromatography eluting with 2:1 v/v ether±petroleum ether
afforded 5c (0.111 g, 67%) which crystallized from ether±
petroleum ether as colorless needles. Mp 180±182 8C.
(Found: C, 72.1; H, 4.8; N, 8.2. C20H16N2O3 requires: C,
72.3; H, 4.85; N, 8.45%); d: 3.24 (ddd, 1H, Jˆ2.4, 7.5,
16.0 Hz, ArCHH), 3.46 (d, 1H, Jˆ16.0 Hz, ArCHH), 3.72
(s, 3H, OCH3), 5.77 (d, 1H, Jˆ7.0 Hz, NCHCO2Me), 6.24
(s, 1H, ArCHN), 7.08±7.21 (m, 2H, ArH), 7.35 (d, 1H,
Jˆ7.7 Hz, ArH), 7.47±7.53 (m, 2H, ArH), 7.63 (dd, 1H,
Jˆ1.1, 7.5 Hz, ArH), 7.84 (dd, 1H, Jˆ0.7, 7.6 Hz, ArH),
7.92 (d, 1H, Jˆ7.5 Hz, ArH) and 8.53 (br, 1H, NH); m/z
(%): 332 (M1, 46), 304 (6), 273 (28), 271 (100) and 245
1260 cm21
.
trans-1-(2-Iodo-phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline-3-carboxylic acid methyl ester 7b and cis-1-
(2-iodo-phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-iso-
quinoline-3-carboxylic acid methyl ester 7c. Prepared by
general procedure C(1) from imine 6b (3.62 g, 8 mmol) and
p-toluenesulphonic acid monohydrate (0.152 g, 0.8 mmol)
over 8 h. The product comprised a 3:2 mixture of 7b and 7c
(1H NMR).
cis isomer 7c: Flash chromatography eluting with 1:2 v/v
ether±hexane afforded 7c (0.88 g, 24%) which crystallized
from ether as colorless prisms. Mp 113±1158C. (Found: C,
50.45; H, 4.55; N, 2.8; I, 28.05. C19H20NO4I requires: C,
50.35; H, 4.45; N, 3.1; I, 28.0%); d: 3.06±3.12 (m, 2H,
ArCH2), 3.63, 3.78 and 3.87 (3£s, 3£3H, 3£OCH3), 3.92
(m, 1H, NCHCO2Me), 5.48 (s, 1H, ArCHN), 6.18 and 6.65
(2£s, 2£1H, ArH), 6.99 (m, 1H, ArH), 7.26±7.28 (m, 2H,
ArH) and 7.87 (d, 1H, Jˆ7.9 Hz, ArH); m/z (%): 453 (M1,
12), 394 (100), 380 (21), 250 (45), 151 (23), 119 (17) and 77
(31); nmax: 3308, 1677, 1465 and 727 cm21
.
[2-(3,4-Dimethoxy-phenyl)-ethyl]-(2-iodo-benzylidene)-
amine 6a. Prepared by general procedure A from
3,4-dimethoxy-phenethyl amine (1.09 g, 6 mmol) and
2-iodobenzaldehyde (1.39 g, 6 mmol). Work up afforded
6a (2.37 g, 100%) which crystallized from benzene as color-
less prisms, mp 70±728C. (Found: C, 51.85; H, 4.7; N, 3.3;
I, 31.9. C17H18NO2I requires: C, 51.65; H, 4.6; N, 3.55; I,
32.1%); d: 2.98 (t, 2H, Jˆ7.2 Hz, ArCH2), 3.84 and 3.86
(2£s, 2£3H, 2£OCH3), 3.87±3.95 (m, 2H, NCH2), 6.75±
7.40 (m, 5H, ArH), 7.82±7.96 (m, 2H, ArH) and 8.29 (s, 1H,
NvCH); m/z (%): 395 (M1, 27), 244 (45), 217 (11), 151
(100), 117 (69) and 90 (29).
(13); nmax: 2948, 1734, 1514 and 1219 cm21
.
3-(3,4-Dimethoxy-phenyl)-2-(2-iodo-benzylidene amino)
propionic acid methyl ester 6b. Prepared by general pro-
cedure A from 3,4-dimethoxyphenylalanine methyl ester
hydrochloride (3.03 g, 11 mmol), 2-iodobenzaldehyde
(2.32 g, 10 mmol) and Et3N (1.21 g, 12 mmol). Work up
afforded 6b (4.08 g, 90%) as a pale yellow gum. d: 3.09
(dd, 1H, Jˆ13.6, 9.2 Hz, ArCHH), 3.29 (dd, 1H, Jˆ13.6,
4.6 Hz, ArCHH), 3.74, 3.78 and 3.82 (3£s, 3£3H,
3£3OCH3), 4.24 (dd, 1H, Jˆ9.3, 4.6 Hz, NCH), 6.66±
6.79 (m, 3H, ArH), 7.12 (dt, 1H, Jˆ1.4, 7.6 Hz, ArH),
7.35 (t, 1H, Jˆ7.5 Hz, ArH), 7.79 (d, 1H, Jˆ8.0 Hz, ArH)
and 7.99±8.07 (m, 2H, ArH and NvCH); m/z (%): 453
(M1, 14), 380 (8), 302 (17), 242 (13), 151 (100), 116 (11)
and 77 (10).
trans isomer 7b: Continued ¯ash chromatography eluting
with 1:2 v/v ether±hexane afforded 7b (1.33 g, 37%)
which crystallized from ether as colorless needles. Mp
117±1198C. (Found: C, 50.35; H, 4.5; N, 2.85; I, 28.05.
C19H20NO4I requires: C, 50.35; H, 4.45; N, 3.1; I, 28.0%);
d: 3.03 (dd, 1H, Jˆ9.0, 15.9 Hz, ArCH2), 3.16 (dd, 1H,
Jˆ4.7, 16.0 Hz, ArCH2), 3.70, 3.73 and 3.89 (3£s, 3£3H,
3£OCH3), 3.71 (m, 1H, NCHCO2Me), 5.52 (s, 1H,
ArCHN), 6.29 and 6.67 (2£s, 2£1H, ArH), 6.73 (dd, 1H,
Jˆ1.7, 7.7 Hz, ArH), 6.95 (dt, 1H, Jˆ1.7, 7.7 Hz, ArH),
7.18 (dt, 1H, Jˆ1.1, 7.5 Hz, ArH) and 7.90 (dd, 1H,
1-(2-Iodo-phenyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-iso-
quinoline 7a. A mixture of imine 6a (2.37 g, 6 mmol),
tri¯uoroacetic acid (40 ml) and benzene (40 ml) was stirred
and boiled under re¯ux for 12 h. The reaction mixture was

R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
6591
Jˆ1.2, 7.9 Hz, ArH); m/z (%): 453 (M1, 34), 394 (100), 326
(45), 250 (67), 190 (53), 119 (15) and 77 (12); nmax: 2956,
mp117±1198C. (Found (HRMS): 365.161140. C20H21NO2
requires: 365.162708); d: 2.94 and 3.30 (2£dd, 2£1H,
Jˆ5.8, 17.3 Hz, ArCH2), 3.49±3.60 (m, 2H, NCH2), 3.67,
3.83 and 3.86 (3£s, 3£3H, 3£OCH3), 4.24 (dd, 1H, Jˆ5.7,
12.4 Hz, NCHCO2Me), 4.98 and 5.21 (2£s, 2£1H,
CvCH2), 5.61 (s, 1H, ArCHN), 6.62 and 6.66 (2£s,
2£1H, ArH), 7.28±7.32 (m, 3H, ArH) and 7.77 (dd, 1H,
Jˆ2.9, 5.4 Hz, ArH); m/z (%): 365 (M1, 7), 306 (100),
205 (8), 149 (94), 115 (7) and 77 (5); nmax: 2956, 1738,
1745, 1514 and 1223 cm21
.
1514 and 1241 cm21
.
2,3-Dimethoxy-6,12b-dihydro-5H-isoindolo[1,2-a]iso-
quinolin-8-one 9a. Prepared by general procedure D from
7a (0.395 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol) and Et3N (0.101 g, 1 mmol) at 1108C
over 16 h. Flash chromatography eluting with 4:1 v/v ether±
petroleum ether afforded 9a (0.153 g, 52%) which crystal-
lized from ethyl acetate as colorless prisms, mp 164±1668C.
(Found: C, 73.2; H, 5.95; N, 4.55. C18H17NO3 requires: C,
73.2; H, 5.8; N, 4.75%); d: 2.78 and 3.01 (2£m, 2£1H,
ArCH2), 3.42 and 4.05 (2£m, 2£1H, NCH2), 3.85 and
3.49 (2£s, 2£3H, 2£OCH3), 5.63 (s, 1H, ArCHN), 6.67
and 7.13 (2£s, 2£1H, ArH) and 7.41±7.89 (m, 4H, ArH);
m/z (%): 295 (M1, 75), 280 (28), 264 (100), 250 (17), 205
(29), 165 (10), 105 (9) and 77 (13); nmax: 2934, 1690, 1513
2,3-Dimethoxy-9-methylene-6,8,9,13b-tetrahydro-5H-
isoquino[1,2-a]isoquinoline 8a. Prepared by general pro-
cedure E from 7a (0.395 g, 1 mmol), Pd(OAc)2 (0.022 g,
0.1 mmol), PPh3 (0.052 g, 0.2 mmol), Et4NCl (0.166 g,
1 mmol) and K2CO3 (0.276 g, 2 mmol) over 16 h. Flash
chromatography eluting with ether afforded 8a (0.279 g,
91%) which crystallized from ethyl acetate as colorless
needles, mp 182±1848C. (Found: C, 77.9; H, 6.7; N, 4.45.
C20H21NO2 requires: C, 78.15; H, 6.9; N, 4.55%); d: 2.76
and 2.94 (2£m, 2£1H, NCH2CH2), 2.92±2.98 (m, 2H,
ArCH2), 3.75 and 4.06 (2£d, 2£1H, Jˆ15.2 Hz, NCH2C),
3.86 (s, 6H, 2£OCH3), 5.03 and 5.12 (2£s, 2£1H, CvCH2),
5.67 (s, 1H, ArCHN), 6.44 and 6.75 (2£s, 2£1H, ArH),
7.12±7.25 (m, 3H, ArH) and 7.68±7.75 (m, 1H, ArH); m/z
(%): 307 (M1, 53), 306 (100), 292 (19), 232 (7), 189 (6),
165 (9), 115 (18) and 77 (10); nmax: 2930, 1609, 1521 and
and 1252 cm21
.
trans-2,3-Dimethoxy-8-oxo-5,6,8,12b±tetrahydro-iso-
indolo[1,2-a]isoquinoline-6-carboxylic acid methyl ester
9b. Prepared by general procedure D from 7b (0.446 g,
1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3 (0.052 g,
0.2 mmol) and Et3N (0.101 g, 1 mmol) at 1108C over
16 h. Flash chromatography eluting with 5:1 v/v ether±
petroleum ether afforded 9b (0.175 g, 50%) which crystal-
lized from ether as pale yellow prisms, mp130±1328C.
(Found: C, 67.9; H, 5.45; N, 3.7. C20H19NO5 requires: C,
68.0; H, 5.5; N, 3.95%); d: 3.13±3.32 (m, 2H, ArCH2), 3.77,
3.86 and 3.92 (3£s, 3£3H, 3£OCH3), 5.28 (t, 1H, Jˆ5.8 Hz,
NCHCO2Me), 5.87 (s, 1H, ArCHN), 6.69 and 7.07 (2£s,
2£1H, ArH), 7.53 (t, 1H, Jˆ7.4 Hz, ArH), 7.66 (t, 1H,
Jˆ7.5 Hz, ArH) and 7.63±7.93 (m, 2H, ArH); m/z (%):
353 (M1, 13), 292 (100), 250 (13), 152 (16), 105 (8) and
1225 cm21
.
trans-2,3-Dimethoxy-9-methylene-6,8,9,13b-tetrahydro-
5H-isoquino[1,2-a]isoquinoline-6-carboxylic acid methyl
ester 8b. Prepared by general procedure E from 7b (0.453 g,
1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3 (0.052 g,
0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3 (0.276 g,
2 mmol) over 16 h. Flash chromatography eluting with 3:2
v/v ether±petroleum ether afforded 8b (0.302 g, 83%)
which crystallized from ether as colorless needles,
mp120±1228C. (Found: C, 72.1; H, 6.5; N, 3.55.
C20H21NO2 requires: C, 72.3; H, 6.35; N, 3.85%); d: 2.84
and 3.00 (2£dd, 2£1H, Jˆ6.8, 15.8 Hz, ArCH2), 3.69±3.96
(m, 3H, NCH2 and NCHCO2Me), 3.73, 3.83 and 3.86 (3£s,
3£3H, 3£OCH3), 5.02 and 5.23 (2£s, 2£1H, CvCH2), 5.69
(s, 1H, ArCHN), 6.66 (s, 2H, ArH), 6.99 (d, 1H, Jˆ7.4 Hz,
ArH), 7.13±7.79 (m, 2H, ArH) and 7.71 (m, 1H, ArH); m/z
(%): 365 (M1, 15), 306 (100), 290 (9), 218 (6), 189 (16),
77 (17); nmax: 3401, 2961, 1696 and 1513 cm21
.
2-(Benzylidene-amino)-3-(1H-indol-3-yl)-propionic acid
methyl ester 10a.10 Prepared by general procedure A
from l-tryptophan methyl ester hydrochloride (2.80 g,
11 mmol), benzaldehyde (1.06 g, 10 mmol) and Et3N
(1.21 g, 12 mmol). Work up afforded 10a (3.07 g, 96%) as
a pale yellow gum. d: 3.24 (dd, 1H, Jˆ8.6, 14.3 Hz,
ArCH2), 3.55 (dd, 1H, Jˆ4.9, 14.4 Hz, ArCH2), 3.73 (s,
3H, OCH3), 4.26 (dd, 1H, Jˆ4.9, 8.6 Hz, CHN), 6.89 (d,
1H, Jˆ2.1 Hz, ArH), 7.07±7.16 (m, 2H, ArH), 7.17±7.40
(m, 4H, ArH), 7.63±7.66 (m, 2H, ArH), 7.85 (s, 1H,
NvCH) and 8.17 (br, 1H, NH); m/z (%): 306 (M1, 7),
247 (5), 177 (5), 130 (100) and 77 (24).
115 (19) and 77 (6); nmax: 2953, 1742 and 1513 cm21
.
cis-2,3-Dimethoxy-9-methylene-6,8,9,13b-tetrahydro-5H-
isoquino[1,2-a]isoquinoline-6-carboxylic acid methyl
ester 8c. Prepared by general procedure E from 7b
(0.453 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 16 h. Flash chromatography eluting
with 1:1 v/v ether±hexane afforded 8c (0.075 g, 21%) which
crystallized from ether±petroleum ether as colorless prisms,
3-(1H-Indol-3-yl)-2-(pyridin-2-ylmethyleneamino)pro-
pionic acid methyl ester 10b. Prepared by general pro-
cedure A from l-tryptophan methyl ester hydrochloride
(2.80 g, 11 mmol), 2-pyridinecarboxaldehyde (1.07 g,
10 mmol) and Et3N (1.21 g, 12 mmol). Work up afforded
10b (2.94 g, 96%) as a pale yellow gum. d: 3.28 (dd, 1H,

6592
R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
Jˆ8.7, 14.5 Hz, ArCH2), 3.64 (dd, 1H, Jˆ5.0, 14.6 Hz,
ArCH2), 3.75 (s, 3H, OCH3), 4.37 (dd, 1H, Jˆ5.2, 8.3 Hz,
CHN), 6.94±7.36 (m, 4H, ArH), 7.60±7.76 (m, 2H, ArH),
8.03±8.07 (m, 2H, ArH and NvCH), 8.18 (br, 1H, NH) and
8.58 (m, 1H, ArH); m/z (%): 307 (M1, 7), 219 (7), 169 (8),
143 (3), 130 (100), 119 (34), 93 (15) and 77 (18).
2-[(Furan-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-pro-
pionic acid methyl ester 11c. Prepared by general pro-
cedure
B
from imine 10c (2.37 g, 8 mmol) and
Na(OAc)3BH (2.37 g, 11.2 mmol). Work up afforded 11c
(2.33 g, 98%) which crystallized from ether as colorless
needles. Mp 85±878C, [a]Dˆ26.4 (1.0, CHCl3). (Found:
C, 68.7; H, 6.1; N, 9.1. C17H18N2O3 requires: C, 68.45; H,
6.1; N, 9.4%); d: 1.88 (br, 1H, NH), 3.14±3.18 (m, 2H,
ArCH2), 3.61 (s, 3H, OCH3), 3.65±3.82 (m, 3H, CHN and
CH2N), 6.08 (d, 1H, Jˆ3.1 Hz, furan-H), 6.24 (dd, 1H,
Jˆ1.9, 3.0 Hz, furan-H), 7.00 (d, 1H, Jˆ2.1 Hz, ArH),
7.06±7.34 (m, 5H, ArH), 7.55 (d, 1H, Jˆ8.2, ArH) and
8.14 (br, 1H, indole-NH); m/z (%): 298 (M1, 2), 239 (4),
2-(Furan-2-ylmethyleneamino)-3-(1H-indol-3-yl)-propionic
acid methyl ester 10c. Prepared by general procedure A
from l-tryptophan methyl ester hydrochloride (2.80 g,
11 mmol), 2-furaldehyde (0.96 g, 10 mmol) and Et3N
(1.21 g, 12 mmol). Work up afforded 10c (2.90 g, 98%) as
a pale yellow gum. d: 3.24 (dd, 1H, Jˆ8.8, 14.4 Hz,
ArCH2), 3.57 (dd, 1H, Jˆ4.9, 14.4 Hz, ArCH2), 3.74 (s,
3H, OCH3), 4.22 (dd, 1H, Jˆ4.9, 8.7 Hz, CHN), 6.41 (dd,
1H, Jˆ1.7, 3.3 Hz, furan-H), 6.64 (d, 1H, Jˆ3.4 Hz, furan-
H), 6.93 (d, 1H, Jˆ2.0 Hz, furan-H), 7.07±7.19 (m, 2H,
ArH), 7.32 (d, 1H, Jˆ7.6 Hz, ArH), 7.48 (s, 1H, ArH),
7.62±7.65 (m, 2H, ArH and NvCH) and 8.30 (br, 1H,
NH); m/z (%): 296 (M1, 2), 237 (2), 167 (5), 143 (3), 130
(100), 103 (11) and 77 (15).
168 (8), 130 (100), 103 (12), 81 (79) and 77 (15); nmax
.
:
3408, 1735, 1458 and 1213 cm21
3-(1H-Indol-3-yl)-2-[(thiophen-2-ylmethyl)amino]-pro-
pionic acid methyl ester 11d. Prepared by general pro-
cedure
B from imine 10d (2.50 g, 8 mmol) and
Na(OAc)3BH (2.37 g, 11.2 mmol). Work up afforded 11d
(2.26 g, 90%) which crystallized from ether±petrolum ether
as colorless needles. Mp 71±738C, [a]Dˆ212.8 (1.0,
CHCl3). (Found: C, 64.7; H, 5.9; N, 9.0; S, 10.3.
C17H18N2O2S requires: C, 64.95; H, 5.75; N, 8.9; S,
10.2%); d: 2.02 (br, 1H, NH), 3.15±3.19 (m, 2H, ArCH2),
3.63 (s, 3H, OCH3), 3.71 (m, 1H, CHN), 3.85 (dd, 1H,
Jˆ0.6, 3.9 Hz, NCH2), 4.04 (dd, 1H, Jˆ0.7, 4.0 Hz,
NCH2), 6.82±6.91 (m, 2H, ArH), 7.01 (d, 1H, Jˆ2.5 Hz,
ArH) 7.09±7.33 (m, 4H, ArH), 7.58 (dd, 1H, Jˆ0.5, 7.7 Hz,
ArH) and 8.13 (br, 1H, indole-NH); m/z (%): 314 (M1, 9),
3-(1H-Indol-3-yl)-2-(thiophen-2-ylmethyleneamino)pro-
pionic acid methyl ester 10d. Prepared by general pro-
cedure A from l-tryptophan methyl ester hydrochloride
(2.80 g, 11 mmol), 2-thiophenecarboxaldehyde (1.12 g,
10 mmol) and Et3N (1.21 g, 12 mmol). Work up afforded
10d (2.81 g, 95%) as a pale yellow gum. d: 3.24 (dd, 1H,
Jˆ8.8, 14.4 Hz, ArCHH), 3.54 (dd, 1H, Jˆ4.8, 14.6 Hz,
ArCHH), 3.73 (s, 3H, OCH3), 4.21 (dd, 1H, Jˆ4.8,
8.8 Hz, CHN), 6.94 (d, 1H, Jˆ2.3 Hz, ArH), 7.00 (dd, 1H,
Jˆ3.7, 15.0 Hz, ArH), 7.07±7.39 (m, 5H, ArH), 7.65 (d, 1H,
Jˆ7.5 Hz, ArH), 7.94 (s, 1H, NvCH) and 8.12 (br, 1H,
NH); m/z (%): 312 (M1, 9), 250 (11), 183 (9), 130 (100),
103 (12) and 77 (24).
255 (22), 184 (37), 130 (100), 97 (85) and 77 (48); nmax
.
:
3410, 2948, 1730, 1454 and 743 cm21
2-Benzyl-1-(2-iodo-phenyl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylic acid methyl ester 12a. Prepared by
general procedure C(2) from 11a (1.85 g, 6 mmol), 2-iodo-
benzaldehyde (1.39 g, 6 mmol) and p-toluenesulphonic acid
monohydrate (0.114 g, 0.6 mmol). Flash chromatography
eluting with 1:12 v/v ether±hexane afforded 12a (2.54 g,
81%) which crystallized from ether±hexane as pale yellow
prisms. Mp 169±1718C. [a]Dˆ2230.8 (1.0, CHCl3).
(Found: C, 59.75; H, 4.5; N, 5.1; I, 24.1. C26H23N2O2I
requires: C, 59.8; H, 4.45; N, 5.35; I, 24.3%); d: 3.22±
3.24 (m, 2H, ArCH2), 3.62 (s, 3H, OCH3), 3.77 and 4.00
(2£d, 2£1H, Jˆ13.8 Hz, NCH2), 3.96 (t, 1H, Jˆ3.9 Hz,
NCHCO2Me), 6.10 (s, 1H, ArCHN), 6.95±7.32 (m, 9H,
ArH), 7.47±7.56 (m, 3H, ArH) and 7.89 (dd, 1H, Jˆ1.1,
8.0 Hz, ArH); m/z (%): 522 (M1, 23), 463 (51), 431 (100),
371 (9), 243 (17), 218 (67) and 91 (80); nmax: 3440, 3058,
2-Benzyl-amino-3-(1H-Indol-3-yl)-propionic acid methyl
ester 11a.11 Prepared by general procedure B from imine
10a (2.45 g, 8 mmol) and Na(OAc)3BH (2.37 g,
11.2 mmol). Work up afforded 11a (2.22 g, 90%) as a
pale yellow gum, which was puri®ed by ¯ash chromato-
graphy eluting with ether. [a]Dˆ28.8 (1.0, CHCl3). d:
1.84 (br, 1H, NH), 3.12±3.18 (m, 2H, ArCH2), 3.62 (s,
3H, OCH3), 3.64±3.83 (m, 3H, CHN and NCH2), 7.02 (d,
1H, Jˆ1.8 Hz, ArH), 7.07±7.23 (m, 5H, ArH), 7.29±7.38
(m, 2H, ArH), 7.52±7.70 (m, 2H, ArH) and 8.10 (br, 1H,
indole-NH); m/z (%): 308 (M1, 2), 249 (6), 178 (20), 130
(100) and 91 (78).
3-(1H-Indol-3-yl)-2-[(pyridin-2-ylmethyl)amino]-propionic
acid methyl ester 11b. Prepared by general procedure B
from imine 10b (2.46 g, 8 mmol) and Na(OAc)3BH (2.37 g,
11.2 mmol). Work up afforded 11b (2.84 g, 93%) as a pale
yellow gum, which was puri®ed by ¯ash chromatography
eluting with ether. [a]Dˆ220.0 (1.0, CHCl3). (Found: C,
69.75; H, 6.45; N, 13.5. C18H19N3O2 requires: C, 69.9; H,
6.2; N,13.6%) d: 3.12±3.29 (m, 2H, ArCH2), 3.63 (s, 3H,
OCH3), 3.70 (m, 1H, CHN), 3.81 and 3.97 (2£d, 2£1H,
Jˆ14.3 Hz, NCH2), 7.03±7.34 (m, 6H, ArH), 7.51±7.57
(m, 2H, ArH), 8.35 (br, 1H, indole-NH) and 8.45 (m, 1H,
ArH); m/z (%): 309 (M1, 1), 250 (6), 201 (10), 179 (64), 130
(100), 93 (55) and 77 (21); nmax: 3175, 2945, 1735 and
1731, 1459 and 734 cm21
.
1-(2-Iodo-phenyl)-2-pyridin-2-ylmethyl-2,3,4,9-tetra-
hydro-1H±b-carboline-3-carboxylic acid methyl ester
12b. Prepared by general procedure C(2) from 11b
(1.85 g, 6 mmol), 2-iodobenzaldehyde (1.39 g, 6 mmol)
and p-toluenesulphonic acid monohydrate (0.114 g,
0.6 mmol). Flash chromatography eluting with 3:2 v/v
ether±hexane afforded 12b (2.21 g, 74%) which crystallized
from chloroform as pale yellow prisms. Mp 277±2798C.
[a]Dˆ2186.8 (1.0, CHCl3). (Found: C, 57.25; H, 4.3; N,
7.8; I, 24.1. C25H22N3O2I requires: C, 57.35; H, 4.25; N,
8.05; I, 24.25%); d: 3.29±3.36 (m, 2H, ArCH2), 3.61 (s,
3H, OCH3), 3.86 and 4.22 (2£d, 2£1H, Jˆ15.3 Hz,
1431 cm21
.

R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
6593
NCH2), 4.02 (t, 1H, Jˆ4.1 Hz, NCHCO2Me), 6.15 (s, 1H,
ArCHN), 6.93 (m, 1H, ArH), 7.04±7.68 (m, 9H, ArH), 7.84
(d, 1H, Jˆ7.9 Hz, ArH) and 8.38 (m, 1H, ArH); m/z (%):
523 (M1, 1), 431 (100), 371 (12), 243 (16), 217 (34), 169 (7)
5.05; S, 6.15. C24H21N2O2SI requires: C, 54.55; H, 4.0; N,
5.3; S, 6.05%); d: 3.27 (m, 2H, ArCH2), 3.63 (s, 3H, OCH3),
3.80 and 4.37 (2£d, 2£1H, Jˆ14.7 Hz, NCH2), 4.14 (t, 1H,
Jˆ4.0 Hz, NCHCO2Me), 6.09 (s, 1H, ArCHN), 6.87±7.33
(m, 7H, ArH), 7.47±7.53 (m, 2H, ArH), 7.59 (dd, 1H,
Jˆ1.8, 7.8 Hz, ArH) and 7.88 (dd, 1H, Jˆ1.2, 8.0 Hz,
ArH); m/z (%): 528 (M1, 11), 469 (15), 431 (64), 371 (9),
243 (13), 218 (11)and 97 (100); nmax: 3440, 2948, 1727,
and 93 (77); nmax: 3393, 2851, 1727, 1431 and 742 cm21
.
1459 and 739 cm21
.
Compound 13a. Prepared by general procedure E from 12a
(0.522 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 40 h. Flash chromatography eluting
with 1:12 v/v ether±petroleum ether afforded 12a (0.317 g,
73%) which crystallized from ether±petrolum ether as
colorless prisms. Mp 207±2098C. [a]Dˆ2100.0 (1.0,
CHCl3). (Found: C, 80.1; H, 6.2; N, 6.2. C29H26N2O2
requires: C, 80.15; H, 6.05; N, 6.45%); d: 3.06±3.27 (m,
2H, ArCH2CH), 3.68 (s, 3H, OCH3), 4.02±4.09 (m, 3H,
CH2CvCH2 and NCHCO2Me), 4.84 and 4.99 (2£d,
2£1H, Jˆ14.3 Hz, NCH2Ph), 5.29 and 5.51 (2£s, 2£1H,
CvCH2), 5.61 (s, 1H, ArCHN), 7.06±7.50 (m, 12H, ArH)
and 7.95 (d, 1H, Jˆ7.6 Hz, ArH); m/z (%): 434 (M1, 20),
375 (22), 343 (100), 283 (27), 257 (44), 128 (7)and 91 (45);
2-Furylmethyl-1-(2-iodo-phenyl)-2,3,4,9-tetrahydro-1H-
b-carboline-3-carboxylic acid methyl ester 12c. Prepared
by general procedure C(2) from 11c (1.79 g, 6 mmol),
2-iodobenzaldehyde (1.39 g, 6 mmol) and p-toluenesul-
phonic acid monohydrate (0.114 g, 0.6 mmol). Flash
chromatography eluting with 1:15 v/v ether±hexane
afforded 12c (2.52 g, 82%) which crystallized from chloro-
form as colorless prisms. Mp 257±2598C. [a]Dˆ2174.0
(1.0, CHCl3). (Found: C, 56.2; H, 4.1; N, 5.2; I, 24.65.
C24H21N2O3I requires: C, 56.25; H, 4.1; N, 5.45; I,
24.75%); d: 3.26±3.27 (m, 2H, ArCH2), 3.63 (s, 3H,
OCH3), 3.69 (m, 1H, NCHCO2Me), 4.03±4.09 (m, 2H,
NCH2), 6.03 (s, 1H, ArCHN), 6.14 (d, 1H, Jˆ3.2 Hz,
furan-H), 6.27 (dd, 1H, Jˆ1.9, 3.1 Hz, furan-H), 6.95±
7.57 (m, 8H, ArH and furan-H), 7.88 (dd, 1H, Jˆ1.1,
8.0 Hz, ArH); m/z (%): 512 (M1, 19), 453 (25), 431 (100),
371 (14), 309 (5), 243 (11), 218 (37), 128 (5) and 81 (47);
n
max: 3058, 1735, 1450 and 735 cm21
.
Compound 13b. Prepared by general procedure E from 12b
(0.523 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 40 h. Flash chromatography eluting
with 1:1 v/v ether±petroleum ether afforded 13b (0.241 g,
55%) as a pale yellow gum. [a]Dˆ2118.4 (1.0, CHCl3).
(Found: C, 76.6; H, 5.85; N, 9.25. C28H25N3O2´(H2O)1/4
requires: C, 76.55; H, 5.75; N, 9.55%; Found (HRMS):
435.194275. C28H25N3O2 requires: 435.194677); d: 3.11±
3.30 (m, 2H, ArCH2CH), 3.70 (s, 3H, OCH3), 4.08 and 4.23
(2£d, 2£1H, Jˆ15.5 Hz, CH2CvCH2), 4.12 (t, 1H,
Jˆ5.8 Hz, NCHCO2Me), 4.83 and 4.97 (2£d, 2£1H,
Jˆ14.3 Hz, NCH2Py), 5.26 and 5.49 (2£s, 2£1H,
CvCH2), 5.60 (s, 1H, ArCHN), 7.04±7.34 (m, 8H, ArH),
7.48 (dd, 1H, Jˆ0.9, 7.0 Hz, ArH), 7.68 (dt, 1H, Jˆ1.7,
7.7 Hz, ArH), 7.77 (d, 1H, Jˆ7.8 Hz, ArH), 7.90 (d, 1H,
Jˆ7.5 Hz, ArH) and 8.51 (m, 1H, ArH); m/z (%): 435 (M1,
2), 376 (4), 343 (100), 283 (51), 256 (25), 119 (10) and 93
n
max: 3393, 2949,1731, 1459 and 739 cm21
.
(50); nmax: 2951, 1730, 1457 and 727 cm21
.
Compound 13c. Prepared by general procedure E from 12c
(0.512 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 40 h. Flash chromatography eluting
with 4:1 v/v ether±petroleum ether afforded 13c (0.261 g,
62%) which crystallized from ethyl acetate as colorless
prisms. Mp 224±226 8C. [a]Dˆ227.2 (1.0, CHCl3).
(Found: C, 75.8; H, 5.55; N, 6.55; C27H24N2O3´(H2O)1/4
requires: C, 75.6; H, 5.75; N, 6.55%; Found (HRMS):
424.176689. C27H24N2O3 requires: 424.178693); d: 3.06±
3.23 (m, 2H, ArCH2CH), 3.64 (s, 3H, OCH3), 3.87±4.11 (m,
3H, CH2CvCH2 and NCHCH2), 4.48 and 5.01 (2£d, 2£1H,
Jˆ14.2 Hz, furan-CH2), 5.36 and 5.58 (2£s, 2£1H,
CvCH2), 5.75 (s, 1H, ArCHN), 6.30 (d, 1H, Jˆ2.9 Hz,
furan-H), 6.36 (d, 1H, Jˆ1.2 Hz, furan-H), 7.03±7.45 (m,
8H, ArH and furan-H) and 7.94 (d, 1H, Jˆ7.6 Hz, ArH); m/z
1-(2-Iodo-phenyl)-2-thienylmethyl-2,3,4,9-tetrahydro-
1H-b-carboline-3-carboxylic acid methyl ester 12d.
Prepared by general procedure C(2) from 11d (1.88 g,
6 mmol), 2-iodobenzaldehyde (1.39 g, 6 mmol) and
p-toluenesulphonic acid monohydrate (0.114 g, 0.6 mmol).
Flash chromatography eluting with 1:15 v/v ether±petrolum
ether afforded 12d (2.69 g, 85%) which crystallized from
ethyl acetate as colorless prisms. Mp 253±2558C.
[a]Dˆ2212.0 (1.0, CHCl3). (Found: C, 54.8; H, 4.15; N,

6594
R. Grigg et al. / Tetrahedron 56 (2000) 6585±6594
(%): 424 (M1, 3), 343 (60), 283 (51), 257 (100), 128 (29)
and 81 (92); nmax: 3054, 1731 and 1454 cm21
Structure re®nement
.
Number of parametersˆ291, isotropic extinction parameter,
xˆ0.007(1), goodness of ®t, sˆ1.101; wR2 (all data)ˆ
0.1678, R1 (`observed' data)ˆ0.0593.
Compound 13d. Prepared by general procedure E from 12d
(0.528 g, 1 mmol), Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3
(0.052 g, 0.2 mmol), Et4NCl (0.166 g, 1 mmol) and K2CO3
(0.276 g, 2 mmol) over 40 h. Flash chromatography eluting
with 1:10 v/v ether±petroleum ether afforded 13d (0.212 g,
48%) which crystallized from ether±petrolum ether as
colorless prisms. Mp 226±2288C. [a]Dˆ2124.4 (1.0,
CHCl3). (Found: C, 73.55; H, 5.7; N, 6.1; S, 7.3.
C27H24N2O2S requires: C, 73.60; H, 5.50; N, 6.35; S,
7.3%); d: 3.06±3.25 (m, 2H, ArCH2CH), 3.67 (s, 3H,
OCH3), 4.11 and 4.28 (2£d, 2£1H, Jˆ14.5 Hz,
CH2CvCH2), 4.14 (t, 1H, Jˆ5.1 Hz, NCHCO2Me), 4.83
and 4.99 (2£d, 2£1H, Jˆ14.2 Hz, NCH2), 5.32 and 5.53
(2£s, 2£1H, CvCH2), 5.69 (s, 1H, ArCHN), 6.94±7.47
(m, 10H, ArH) and 7.98 (d, 1H, Jˆ7.4 Hz, ArH); m/z (%):
440 (M1, 5), 381 (8), 343 (100), 257 (39), 128 (8) and 97
A
supplementary dataset, which includes hydrogen
co-ordinates, all thermal parameters and complete sets of
bond lengths and angles, have been deposited at the
Cambridge Crystallographic Data Centre and are available
on request.
Acknowledgements
We thank the ORS for a scholarship (J. Z.) and SmithKline
Beecham Pharmaceuticals and Leeds University for
support.
(83); nmax: 2948, 1726, 1450 and 735 cm21
.
References
1. Grigg, R.; Thornton-Pett, M.; Yoganathan, G. Tetrahedron
1999, 55, 8129±8140.
Single crystal X-ray diffraction analysis of 13d
2. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 1797±1892 (and
references therein).
Crystallographic data were measured on a Stoe STADI
4-circle diffractometer using v ±u scans and CuKa radia-
Ê
3. Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, S. G.;
Yamanaka, E.; Hutchins, L.; Pierri, M. D.; Cook, J. M. J. Org.
Chem. 1979, 44, 535±545.
tion (lˆ1.54184 A). The structure was solved by direct
methods using shelxs-86(2)12 and was re®ned by full-
matrix least-squares (based on F2) using shelxl-93(1).13
The
weighting
scheme
used
wˆ[s2(F2o)1
4. Nakagawa, M.; Fukushima, H.; Kawate, T.; Hongu, M.;
Kodato, S.; Une, T.; Taniguchi, M.; Hino, T. Tetrahedron Lett.
1986, 27, 3235; Harrison, D. M.; Sharma, R. B. Tetrahedron
Lett. 1986, 27, 521; Bailey, P. D.; Hollinshead, S. P.; McLay,
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Wood, S. D. J. Chem. Soc., Perkin Trans. 1 1993, 431.
5. Grigg, R.; Sridharan, V.; Terrier, C. Tetrahedron Lett. 1996, 37,
4221±4229; Grigg, R.; Savic, V. Tetrahedron Lett. 1996, 37,
6565±6568; Grigg, R.; Savic, V. Tetrahedron Lett. 1997, 38,
1825±1828; Grigg, R.; Sridharan, V.; Xu, L. H. Chem. Commun.
1995, 1903±1904.
(0.0911P)211.0092P]21 where Pˆ(Fo212Fc2)/3. All non-
hydrogen atoms were re®ned with anisotropic displace-
ment parameters whilst hydrogen atoms were
constrained to predicted positions using
a riding
model. Re®nement included an isotropic extinction
parameter, x, so that Fc0 ˆkFc[110.001pxpF2cpl3]21/4
where k is the overall scale factor. The residuals wR2
and
R1,
given
below,
are
de®ned
as
P
P
P
wR2ˆ( [w(Fo2F2c)2]/ [wFo4])1/2 and R1 ˆ uuFou 2 uFcuu
P
Crystal data for 13d
/ uFou.
6. Grigg, R.; Sridharan, V. Tetrahedron Lett. 1993, 34, 7471±
7474; Heuman, A.; Reylier, H. Tetrahedron 1996, 52, 9289±
9296; Negishi, E. I.; Coperet, C.; Ma, S.; Liou, S. Y.; Liu, F.
Chem Rev. 1996, 96, 365±393.
C27H24N2O2S, 0.36£0.28£0.19 mm, Mˆ440.54, triclinic,
space group P-1, aˆ9.0602(3), bˆ11.4771(4), cˆ
7. Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J. M. J. Org.
Chem. 1981, 46, 164.
Ê
12.2957(3) A, aˆ93.053(4)8, bˆ109.452(3)8, gˆ
8. Zhang, L.-H.; Cook, J. M. Heterocycles 1988, 27, 1357 (see also
p 2795).
108.441(3)8, Vˆ1125.56(6) A , Zˆ2, Dcˆ1.3 Mg m23
,
Ê 3
mˆ1.49 mm21, F(000)ˆ464, Tˆ190 K.
9. Perrin, D. D.; Armarego, W. L. F. Puri®cation of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
Data collection
10. Waldmann, H.; Braun, M.; Weymann, M.; Gewehr, M.
Tetrahedron 1993, 49, 397±416.
Ê
Graphite monochromated CuKa radiation, lˆ1.54184 A,
scan speeds 1.5±8.08 min21, v scan widths 1.0581a-
doublet splitting, 7.74 ,2u,128.928; 3479 Unique data
collected of which 2861 with Fo.4.0s(Fo) were considered
`observed'.
11. Yoshioka, T.; Mohri, K.; Oikawa, Y.; Yonemitsu, O. J. Chem.
Res. 1981, 7, 2252±2281.
12. Sheldrick, G. M. Acta Crystallogr. A 1990, 46, 467±473.
13. Sheldrick, G. M. shelxl 93; Program for re®nement of crystal
È
structures, University of Gottingen, 1993.