Synthesis of homocarbonyltopsentine derivatives

Article abstract of DOI:10.1055/s-2004-834905

Homocarbonyltopsentines I are known to exhibit interesting anti-inflammatory activity in vivo. In order to study the role of the heterocycles in the modulation of their activity, several analogues in which indoles were replaced either by substituted indol

Full text of DOI:10.1055/s-2004-834905

136
PAPER
Synthesis of Homocarbonyltopsentine Derivatives
Synthesis of
H
om
y
ocarbonylto
r
psentine
i
Deriva
l
tives Montagne, Guy Fournet, Benoît Joseph*
Laboratoire de Chimie Organique 1, UMR-CNRS 5181, Université Claude Bernard – Lyon 1, CPE - Bâtiment 308, 43 Boulevard
du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72431214; E-mail: benoit.joseph@univ-lyon1.fr
Received 14 July 2004; revised 2 September 2004
Abstract: Homocarbonyltopsentines I are known to exhibit inter-
esting anti-inflammatory activity in vivo. In order to study the role
of the heterocycles in the modulation of their activity, several ana-
logues in which indoles were replaced either by substituted indoles
or by bioisosteric heterocycles such as pyrrolo[2,3-b]pyridine, ben-
zo[b]thiophene and pyridine were synthesised. The synthesis is
based on selective halogen–metal exchange on triiodoimidazole 1
and subsequent addition to formylated heterocycles.
Key words: indoles, metalation, regioselectivity, addition reac-
tions, palladium
Many naturally occurring bis-indole alkaloids such as
topsentins, dragmacidins, rhopaladins and hamacanthins,
extracted from marine organisms and described to date,
Figure 1
exhibit pharmacological properties.1 Among them, a
closely related structure called homocarbonyltopsentine I
was reported in the literature, which showed potent anti-
inflammatory activity in vivo.2
The first step of the synthesis was realised by reaction of
n-BuLi with triiodoimidazole 1 which produced selective-
ly the carbanion at C-2.6 Addition of formylated heterocy-
cles 2 to the carbanion intermediate afforded alcohols 3 in
good yields (Scheme 2). Only in the case of 1-tert-butyl-
oxycarbonyl-3-formylpyrrolo[2,3-b]pyridine, low reac-
tion yield was observed (24%, not described). Alcohols 3
were then oxidised with MnO2 to produce the correspond-
ing ketones 4 (Table 1). After the first part of the synthesis
was achieved, the derivatives 4a–c were selected to reach
the final compounds II.
In a previous paper, we have described a general approach
to prepare this bis-indole skeleton via selective halogen–
metal exchange reactions on triiodoimidazole followed by
addition to formylated indoles.3 In our ongoing research
work, we investigated the synthesis of compounds dis-
playing the general structure II, in order to determine the
importance of the nature of the substituent on the indole
moiety and the nature of the heterocycle linked to the po-
sition 4 of the imidazole nucleus through a carbonyl func-
tion (Figure 1).
Table 1 Yields of Compounds 3 and 4
By this synthetic methodology, which allowed us to
switch easily from one heterocycle to another, a wide
range of homocarbonyltopsentine derivatives or ana-
logues can be prepared in sufficient amount for biological
assays (Scheme 1). Thus, selective halogen–metal ex-
change reactions were performed on triiodoimidazole 14
(EOM = ethoxymethyl) in order to prepare highly nucleo-
philic species which can then react with conveniently sub-
stituted and protected formylated heterocycles (Het-CHO
and Het¢-CHO). According to literature procedures, 3-
formylindoles 2a,b and 2c5 were prepared in our laborato-
ry (Scheme 1). Other aldehydes such as 3-formylpyridine
(2d) and 3-formylbenzothiophene (2e) are commercially
available.
Aldehyde
Product 3
Yield (%)
Product 4
Yield (%)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
75
68
73
90
43
4a
4b
4c
4d
4e
91
90
90
85
92
Using the same conditions as for the first substitution, the
alcohols 5 were obtained in good yields from 4a–c by se-
lective iodine–lithium exchange at C-4 and reaction with
aldehydes 2c–e (Scheme 3, Table 2).6 The alcohols were
subsequently oxidised to produce the diketones 6 in fair
yields (Table 2).
SYNTHESIS 2005, No. 1, pp 0136–0146
x
x
.
x
x
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4
Advanced online publication: 02.11.2004
DOI: 10.1055/s-2004-834905; Art ID: T08504SS
© Georg Thieme Verlag Stuttgart · New York
The last iodine on compounds 6 was then removed by hy-
drogenolysis in the presence of palladium on charcoal as

PAPER
Synthesis of Homocarbonyltopsentine Derivatives
137
Scheme 1
Scheme 2 Reagents and conditions: i. n-BuLi (1 equiv), THF,
–78 °C, 5 min then 2 (1.1 equiv), 45 min; ii. MnO2, CH2Cl2, r.t., 4 h.
catalyst and potassium carbonate as proton scavenger
(Scheme 3). Under these conditions, the benzyl group of
6a was not affected. For 6d, we isolated 7d in 55% yield
along with the by-product 7f (20%) in which the pyridine
nucleus was reduced into 1,2,3,4-tetrahydropyridine
(Scheme 3). Except this example, compounds 7 were iso-
lated in 80–89% yields.
Final compounds 9 were obtained by successive deprotec-
tion of the tert-butyloxycarbonyl and the ethoxymethyl
groups (Scheme 4). Thus, derivatives 7a–e were, first
treated with aqueous 1 N NaOH in 1,4-dioxane at 70 °C
for 30 minutes to afford compounds 8a–e in good yields
(Table 3). The latter, when heated in the presence of aque-
ous 1 N HCl in 1,4-dioxane for 30 minutes gave 9a–e.
Table 2 Yields of Compounds 5–7
Het¢
Y
Yield (%)
Scheme 3 Reagents and conditions: i. n-BuLi (1 equiv), THF,
–78 °C, 5 min then 2 (1.1 equiv), 45 min; ii. MnO2, CH2Cl2, r.t., 5 h;
iii. H2 (15 bar), 10% Pd/C, K2CO3, EtOH–CH2Cl2, overnight, r.t.
5
6
7
2c
2c
2c
2d
2e
OBn
OMe
H
5a 61
5b 61
5c 71
5d 70
5e 65
6a 84
6b 99
6c 84
6d 82
6e 65
7a 89
7b 93
7c 85
7d 55
7e 80
Close derivatives of 9d have been reported as potent anti-
cancer agents.7 Synthesis of homocarbonyltopsentine Ia
was finally achieved by hydrogenolysis (HCO2NH4, 10%
Pd/C, EtOH, reflux, 1 h) of the benzyl protecting group of
9a in 91% yield.
H
H
Synthesis 2005, No. 1, 136–146 © Thieme Stuttgart · New York

138
C. Montagne et al.
PAPER
Scheme 4 Reagents and conditions: i. 1 N NaOH, 1,4-dioxane, 70 °C, 30 min; ii. 1 N HCl, 1,4-dioxane, 70 °C, 30 min; iii. 10% Pd/C,
HCO2NH4, EtOH, reflux, 1 h, 91%.
Iodo derivative 10 was also prepared from 6c in 56% yield
(Scheme 5). Taking advantage of iodine on the imidazole
ring of compounds 6, introduction of a third substituent on
the imidazole by palladium-mediated cross-coupling re-
action can be done giving access to a wide variety of de-
rivatives. From our part, only a Suzuki reaction8 was
explored in our laboratory (Scheme 5). According to the
classical method, commercially available boronic acids
(phenylboronic acid, 2-thienylboronic acid, 2-furylboron-
ic acid and 1-tert-butyloxycarbonyl-2-pyrrolylboronic
acid9) were coupled to derivative 6c in the presence of tet-
rakis(triphenylphosphine)palladium to afford 11a–d in
good yields (Table 4). As a final example, two successive
deprotection reactions were performed on 11a to afford 12
in 83% yield (Scheme 5). Surprisingly, we observed a
complete degradation of 11d when submitted to the
deprotection reactions.
In summary, we have prepared homocarbonyltopsentine
Ia and several analogues or derivatives. These compounds Na2CO3, toluene–EtOH, 80 °C, 1.5–48 h; ii. aq 1 N NaOH, 1,4-dioxa-
Scheme 5 Reagents and conditions: i. ArB(OH)2, Pd(PPh3)4,
ne, 70 °C, 30 min; iii. aq 1 N HCl, 1,4-dioxane, 70 °C, 45 min, 10:
56%, 12: 83%.
are currently evaluated for anti-inflammatory activity and
the results will be reported in due course.
Bruker Avance 300 spectrometer. Chemical shifts are expressed in
Melting points were obtained on a Büchi capillary instrument and
are uncorrected. IR spectra were recorded on a Perkin-Elmer 681 IR
parts per million (ppm) relative to TMS. Mass spectra were record-
ed on a Perkin-Elmer SCIEX API spectrometer. Elemental analyses
were performed on a Thermoquest Flash 1112 series EA analyser.
TLC was conducted on precoated silica gel plates (Merck 60F254)
1
spectrophotometer. H and 13C NMR spectra were recorded on a
Table 3 Yields of Compounds 8 and 9
Table 4 Yields of Compounds 11
8
Yield (%)
9
Yield (%)
Ar
11
Yield (%)
8a
8b
8c
8d
8e
85
89
89
97
80
9a
9b
9c
9d
9e
83
85
90
96
88
Ph
11a
11b
11c
11d
92
95
96
89
2-thienyl
2-furyl
2-(1-Boc)pyrrolyl
Synthesis 2005, No. 1, 136–146 © Thieme Stuttgart · New York

PAPER
Synthesis of Homocarbonyltopsentine Derivatives
IR (film): 3400, 1730, 1620 cm–1.
139
and the spots were visualised under UV light. Flash chromatogra-
phy was carried out on column using flash silica gel 60 Merck (40–
63 mm) using the indicated solvents [petroleum ether (PE): bp 40–
60 °C]. All reactions requiring anhydrous conditions were conduct-
ed in flame-dried apparatus. Boronic acids were purchased from
Lancaster or Sigma-Aldrich.
1H NMR (300 MHz, CDCl3): d = 1.06 (t, 3 H, J = 7.0 Hz, CH3), 1.66
(s, 9 H, 3 CH3), 3.36 (d, 2 H, J = 7.0 Hz, CH2), 4.89 (br s, 1 H, OH),
5.13 (s, 2 H, CH2O), 5.32 (AB system, 2 H, J = 11.9 Hz, CH2N),
6.25 (br s, 1 H, CHOH), 6.91 (dd, 1 H, J = 2.2, 8.7 Hz, H-5), 7.26
(d, 1 H, J = 8.7 Hz, H-4), 7.33–7.48 (m, 5 H, C6H5), 7.59 (s, 1 H, H-
2), 7.83 (br s, 1 H, H-7).
tert-Butyl 6-Benzyloxy-3-formyl-1H-indole-1-carboxylate (2a);
Typical Procedure
13C NMR (75 MHz, CDCl3): d = 14.8 (CH3), 28.2 (3 CH3), 64.5
(CH2), 70.4 (CH2), 76.7 (CH2), 84.0 (C), 84.8 (C), 94.9 (C), 100.8
(CH), 112.9 (CH), 119.9 (C), 120.3 (CH), 122.1 (C), 122.7 (CH),
127.6 (2 CH), 127.9 (CH), 128.6 (3 CH), 136.9 (C), 137.1 (C),
149.7 (C), 153.7 (C), 157.3 (C=O).
A solution of 6-benzyloxyindole-3-carboxaldehyde10 (232 mg, 0.92
mmol), Boc2O (409 mg, 1.86 mmol) and a catalytic amount of
DMAP (5 mg) in MeCN (15 mL) was stirred overnight at r.t. After
evaporation of the solvent, the residue was partitioned between
EtOAc (20 mL) and H2O (20 mL). The two layers were separated
and the aqueous phase was extracted with EtOAc (10 mL). The
combined organic extracts were dried (MgSO4) and evaporated in
vacuo. The oily residue crystallised upon addition of pentane to give
2a (321 mg, 99%); mp 118–119 °C (pentane).
MS (ESI): m/z = 730 (M + H+).
Anal. Calcd for C27H29I2N3O5 (729.36): C, 44.46; H, 4.01; N, 5.76.
Found: C, 44.13; H, 4.17; N, 5.90.
tert-Butyl 3-[(1-Ethoxymethyl-4,5-diiodo-1H-imidazol-2-yl)hy-
droxymethyl]-6-methoxy-1H-indole-1-carboxylate (3b)
Chromatography eluent: PE–EtOAc (6:4); yield: 68%; foam.
IR (KBr): 3140, 2800, 2720, 1740, 1670 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.69 (s, 9 H, 3 CH3), 5.14 (s, 2 H,
OCH2), 7.08 (dd, 1 H, J = 2.1, 8.7 Hz, H-5), 7.31–7.48 (m, 5 H,
C6H5), 7.82 (d, 1 H, J = 2.1 Hz, H-7), 8.12 (s, 1 H, H-2), 8.15 (d, 1
H, J = 8.7 Hz, H-4), 10.05 (s, 1 H, CHO).
IR (film): 3420, 1730, 1615 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (t, 3 H, J = 7.0 Hz, CH3), 1.66
(s, 9 H, 3 CH3), 3.40–3.50 (m, 2 H, CH2), 3.85 (s, 3 H, OCH3), 3.86
(br s, 1 H, OH), 5.16–5.27 (m, 2 H, CH2N), 6.17 (d, 1 H, J = 8.5 Hz,
CHOH), 6.81 (d, 1 H, J = 8.7 Hz, H-5), 7.24 (d, 1 H, J = 8.7 Hz, H-
4), 7.52 (s, 1 H, H-2), 7.69 (br s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 28.1 (3 CH3), 70.4 (OCH2), 85.6
(C) , 100.5 (CH), 114.4 (CH), 120.0 (C), 121.7 (C), 122.7 (CH),
127.6 (2 CH), 128.1 (CH), 128.6 (2 CH), 135.6 (CH), 136.9 (C),
137.1 (C), 148.9 (C), 158.0 (C=O), 185.8 (C=O).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 28.1 (3 CH3), 55.5
(CH3), 64.2 (CH2), 64.4 (CH), 76.5 (CH2), 83.7 (C), 84.8 (C), 94.6
(C), 99.3 (CH), 112.1 (CH), 119.9 (C), 120.2 (CH), 121.8 (C), 122.2
(CH), 136.7 (C), 149.6 (C), 153.7 (C), 157.9 (C=O).
MS (ESI): m/z = 352 (M + H+).
Anal. Calcd for C21H21NO4 (351.41): C, 71.78; H, 6.02; N, 3.91.
Found: C, 72.06; H, 5.91; N, 4.12.
MS (ESI): m/z = 654 (M + H+).
tert-Butyl 3-Formyl-6-methoxy-1H-indole-1-carboxylate (2b)
According to the procedure described for 2a, compound 2b was pre-
pared from 6-methoxyindole-3-carboxaldehyde11 in 97% yield as a
solid; mp 111–112 °C (pentane).
Anal. Calcd for C21H25I2N3O5 (653.26): C, 38.61; H, 3.86; N, 6.43.
Found: C, 38.88; H, 3.92; N, 6.28.
tert-Butyl 3-[(1-Ethoxymethyl-4,5-diiodo-1H-imidazol-2-yl)hy-
droxymethyl]indole-1-carboxylate (3c)
IR (KBr): 3140, 2800, 2720, 1740, 1670 cm–1.
1H NMR (CDCl3): d = 1.71 (s, 9 H, 3 CH3), 3.89 (s, 3 H, OCH3),
6.99 (dd, 1 H, J = 2.1, 8.7 Hz, H-5), 7.72 (d, 1 H, J = 2.1 Hz, H-7),
8.11 (s, 1 H, H-2), 8.14 (d, 1 H, J = 8.7 Hz, H-4), 10.04 (s, 1 H,
CHO).
Chromatography eluent: PE–EtOAc (85:15); yield: 73%; solid; mp
168–169 °C (Et2O).
IR (KBr): 3218, 1734, 1611 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.11 (t, 3 H, J = 7.0 Hz, CH3), 1.67
(s, 9 H, 3 CH3), 3.44 (q, 2 H, J = 7.0 Hz, CH2), 3.82 (d, 1 H, J = 7.1
Hz, OH), 5,22 (AB system, 2 H, J = 7.0 Hz, CH2N), 6.22 (d, 1 H,
J = 7.1 Hz, CHOH), 7.18 (t, 1 H, J = 8.0 Hz, H-5), 7.31 (t, 1 H,
J = 8.0 Hz, H-6), 7.42 (d, 1 H, J = 8.0 Hz, H-4), 7.65 (s, 1 H, H-2),
8.11 (d, 1 H, J = 8.0 Hz, H-7).
13C NMR (CDCl3): d = 28.2 (3 CH3), 55.7 (OCH3), 85.6 (C), 99.3
(CH), 113.8 (CH), 119.8 (C), 121.8 (C), 122.7 (CH), 135.6 (CH),
137.2 (C), 149.0 (C), 159.0 (C=O), 185.9 (C=O).
MS (ESI): m/z = 276 (M + H+).
Anal. Calcd for C15H17NO4 (275.31): C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.21; H, 6.12; N, 4.99.
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 28.2 (3 CH3), 64.5
(CH2 + CH), 77.0 (CH2), 84.1 (C), 84.8 (C), 94.8 (C), 115.3 (CH),
119.8 (CH + C), 123.0 (CH), 123.9 (CH), 124.8 (CH), 128.1 (C),
135.8 (C), 149.6 (C), 153.6 (C).
First Coupling: Reaction of Triiodoimidazole 1 with Formylat-
ed Heterocycles 2; General Procedure
MS (ESI): m/z = 624 (M + H+).
At –78 °C and under N2, a solution of 2.3 M of n-BuLi in hexanes
(1.1 mmol) was added dropwise to a solution of 1 (504 mg, 1 mmol)
in anhyd THF (10 mL). After stirring for 5 min, compound 2 (1.1
mmol) in anhyd THF (5 mL) was added. The final solution was
stirred at –78 °C for 1 h. The reaction was hydrolysed by the addi-
tion of sat. aq NH4Cl solution. The solution was extracted with
CH2Cl2 (2 × 10 mL). The organic phases were combined, dried
(MgSO4), and evaporated in vacuo. The crude residue was purified
by column chromatography to afford derivative 3.
Anal. Calcd for C20H23I2N3O4 (623.23): C, 38.54; H, 3.72; N, 6.74.
Found: C, 38.86; H, 3.90; N, 6.87.
(1-Ethoxymethyl-4,5-diiodo-1H-imidazol-2-yl)pyridin-3-yl-
methanol (3d)
Chromatography eluent: CH2Cl2–MeOH (97:3); yield: 90%; foam.
IR (film): 3150, 1580, 1479 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, 3 H, J = 7.0 Hz, CH3), 3.24
(q, 2 H, J = 7.0 Hz, CH2), 5.28 (AB system, 2 H, J = 10.7 Hz,
CH2N), 6.07 (s, 1 H, CHOH), 7.23 (dd, 1 Hpyr, J = 4.9, 7.9 Hz), 7.70
(d, 1 Hpyr, J = 7.9 Hz), 8.40 (d, 1 Hpyr, J = 4.9 Hz), 8.56 (br s, 1 Hpyr).
tert-Butyl 3-[(1-Ethoxymethyl-4,5-diiodo-1H-imidazol-2-yl)hy-
droxymethyl]-6-benzyloxy-1H-indole-1-carboxylate (3a)
Chromatography eluent: PE–EtOAc (7:3); yield: 75%; foam.
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C. Montagne et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 64.2 (CH2), 67.4 (CH),
76.6 (CH2), 85.3 (C), 95.1 (C), 123.4 (CH), 134.7 (CH), 136.3 (C),
147.4 (CH), 148.4 (CH), 153.7 (C).
(CH), 113.6 (CH), 117.5 (C), 121.8 (C), 123.0 (CH), 136.3 (CH +
C), 148.3 (C), 149.1 (C), 158.4 (C=O), 176.9 (C=O).
MS (ESI): m/z = 652 (M + H+).
MS (ESI): m/z = 486 (M + H+).
Anal. Calcd for C21H23I2N3O5 (651.24): C, 38.73; H, 3.56; N, 6.45.
Found: C, 39.01; H, 3.46; N, 6.52.
Anal. Calcd for C12H13I2N3O2 (485.07): C, 29.71; H, 2.70; N, 8.66.
Found: C, 29.55; H, 2.65; N, 8.75.
tert-Butyl 3-(1-Ethoxymethyl-4,5-diiodo-1H-imidazole-2-car-
bonyl)indole-1-carboxylate (4c)
Chromatography eluent: PE–EtOAc (9:1); yield: 90%; solid; mp
160–161 °C (Et2O).
Benzo[b]thiophen-3-yl-(1-ethoxymethyl-4,5-diiodo-1H-imida-
zol-2-yl)methanol (3e)
Chromatography eluent: PE–EtOAc (85:15); yield: 43%; solid; mp
159–161 °C (EtOAc–PE).
IR (KBr): 1726, 1626, 1606, 1452 cm–1.
IR (KBr): 3480, 1596, 1485 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, 3 H, J = 7.0 Hz, CH3), 1.72
(s, 9 H, 3 CH3), 3.61 (q, 2 H, J = 7.0 Hz, CH2), 6.01 (s, 2 H, CH2),
7.38–7.40 (m, 2 H, H-5, H-6), 8.17–8.20 (m, 1 H, H-4), 8.43–8.47
(m, 1 H, H-7), 9.14 (s, 1 H, H-2).
1H NMR (300 MHz, CDCl3): d = 1.04 (t, 3 H, J = 7.0 Hz, CH3), 3.33
(q, 2 H, J = 7.0 Hz, CH2), 4.26 (d, 1 H, J = 7.0 Hz, OH), 5.17 (s, 2
H, CH2N), 6.33 (d, 1 H, J = 7.0 Hz, CHOH), 7.31–7.37 (m, 2 H, H-
5, H-6), 7.49 (s, 1 H, H-2), 7.73–7.78 (m, 1 H, H-4), 7.81–7.87 (m,
1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 15.0 (CH3) 28.1 (3 CH3), 64.7
(CH2), 77.8 (CH2), 85.4 (C), 92.3 (C), 97.8 (C), 115.1 (CH), 117.5
(C), 122.6 (CH), 124.6 (CH), 125.6 (CH), 128.4 (C), 135.3 (C),
137.5 (CH), 148.4 (C), 149.0 (C), 176.9 (C=O).
13C NMR (75 MHz, CDCl3): d = 14.8 (CH3), 64.5 (CH2), 66.4 (CH),
76.8 (CH2), 84.9 (C), 95.0 (C), 122.5 (CH), 122.9 (CH), 124.6 (2
CH), 124.8 (CH), 124.7 (C), 136.9 (C), 141.0 (C), 153.5 (C).
MS (ESI): m/z = 622 (M + H+).
MS (ESI): m/z = 541 (M + H+).
Anal. Calcd for C20H21I2N3O4 (621.22): C, 38.67; H, 3.41; N, 6.76.
Found: C, 38.34; H, 3.28; N, 6.73.
Anal. Calcd for C15H14I2N2O2S (540.16): C, 33.35; H, 2.61; N, 5.19.
Found: C, 33.30; H, 2.75; N, 5.30.
(1-Ethoxymethyl-4,5-diiodo-1H-imidazol-2-yl)-pyridin-3-yl-
methanone (4d)
Chromatography eluent: CH2Cl2; yield: 85%; solid; mp 133–134 °C
(Et2O).
Oxidation of Alcohols 3 to Ketones 4; General Procedure
A solution of 3 (0.65 mmol) and MnO2 (2.14 g, 24.64 mmol) in
CH2Cl2 (18 mL) was stirred at r.t. for 4 h. MnO2 was removed by
filtration on Celite and the filtrate was evaporated in vacuo. Product
4 was isolated either by crystallisation or by column chromatogra-
phy.
IR (KBr): 1632, 1595, 1574, 1479 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, 3 H, J = 7.0 Hz, CH3), 3.61
(q, 2 H, J = 7.0 Hz, CH2), 5.96 (s, 2 H, CH2N), 7.43 (dd, 1 Hpyr
,
J = 4.9, 8.0 Hz), 7.70 (d, 1 Hpyr, J = 8.0 Hz), 8.79 (dd, 1 Hpyr, J = 1.6,
4.9 Hz), 9.40 (d, 1 Hpyr, J = 1.6 Hz).
tert-Butyl 3-(1-Ethoxymethyl-4,5-diiodo-1H-imidazole-2-car-
bonyl)-6-benzyloxy-1H-indole-1-carboxylate (4a)
Chromatography eluent: PE–EtOAc (8:2); yield: 91%; foam.
13C NMR (75 MHz, CDCl3): d = 15.0 (CH3), 64.9 (CH2), 78.2
(CH2), 95.3 (C), 98.9 (C), 123.2 (CH), 132.0 (CH), 138.4 (2 CH),
147.2 (C), 153.3 (C), 180.6 (C=O).
IR (film): 1745, 1625, 1530, 1420 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.18 (t, 3 H, J = 7.1 Hz, CH3), 1.70
(s, 9 H, 3 CH3), 3.60 (q, 2 H, J = 7.1 Hz, CH2), 5.15 (s, 2 H, CH2O),
6.00 (s, 2 H, CH2N), 7.08 (dd, 1 H, J = 2.2, 8.8 Hz, H-5), 7.30–7.49
(m, 5 H, C6H5), 7.87 (d, 1 H, J = 2.2 Hz, H-7), 8.32 (d, 1 H, J = 8.8
Hz, H-4), 9.01 (s, 1 H, H-2).
MS (ESI): m/z = 484 (M + H+).
Anal. Calcd for C12H11I2N3O2 (483.05): C, 29.84; H, 2.30; N, 8.70.
Found: C, 30.11; H, 2.44; N, 8.56.
13C NMR (75 MHz, CDCl3): d = 15.0 (CH3), 28.1 (3 CH3), 64.6
(CH2), 70.3 (CH2), 77.7 (CH2N), 85.1 (C), 92.2 (C), 97.7 (C), 100.3
(CH), 114.1 (CH), 117.4 (C), 122.1 (C), 123.1 (CH), 127.5 (2 CH),
127.9 (CH), 128.5 (2 CH), 136.1 (C), 136.3 (CH), 136.9 (C), 148.2
(C), 148.9 (C), 157.5 (C=O), 176.3 (C=O).
Benzo[b]thiophen-3-yl-(1-ethoxymethyl-4,5-diiodo-1H-imida-
zol-2-yl)methanone (4e)
Chromatography eluent: CH2Cl2; yield: 92%; foam.
IR (film): 1635, 1490 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.18 (t, 3 H, J = 7.0 Hz, CH3), 3.61
(q, 2 H, J = 7.0 Hz, CH2), 5.94 (s, 2 H, CH2N), 7.41 (t, 1 H, J = 7.5
Hz, H5), 7.50 (t, 1 H, J = 7.5 Hz, H-6), 7.87 (d, 1 H, J = 7.5 Hz, H-
4), 8.75 (d, 1 H, J = 7.5 Hz, H-7), 9.26 (s, 1 H, H-2).
MS (ESI): m/z = 728 (M + H+).
Anal. Calcd for C27H27I2N3O5 (727.34): C, 44.59; H, 3.74; N, 5.78.
Found: C, 44.74; H, 3.66; N, 5.70.
13C NMR (75 MHz, CDCl3): d = 15.0 (CH3), 64.7 (CH2), 78.0
(CH2), 93.0 (C), 98.1 (C), 122.4 (CH), 125.3 (CH), 125.5 (CH),
125.9 (CH), 132.1 (C), 137.5 (C), 139.3 (C), 143.5 (C), 148.4 (C),
175.8 (C=O).
tert-Butyl 3-(1-Ethoxymethyl-4,5-diiodo-1H-imidazole-2-car-
bonyl)-6-methoxy-1H-indole-1-carboxylate (4b)
Chromatography eluent: PE–EtOAc (9:1); yield: 90%; solid; mp
147–148 °C (Et2O–pentane).
MS (ESI): m/z = 539 (M + H+).
IR (KBr): 1745, 1620, 1530 cm–1.
Anal. Calcd for C15H12I2N2O2S (538.15): C, 33.48; H, 2.25; N, 5.21.
Found: C, 33.23; H, 2.27; N, 5.15.
1H NMR (300 MHz, CDCl3): d = 1.18 (t, 3 H, J = 7.1 Hz, CH3), 1.71
(s, 9 H, 3 CH3), 3.60 (q, 2 H, J = 7.1 Hz, CH2), 3.89 (s, 3 H, OCH3),
5.99 (s, 2 H, CH2N), 6.99 (dd, 1 H, J = 2.2, 8.7 Hz, H-5), 7.75 (d, 1
H, J = 2.2 Hz, H-7), 8.29 (d, 1 H, J = 8.7 Hz, H-4), 9.00 (s, 1 H, H-
2).
Second Coupling: Reaction of Diodoimidazoles 4 with Formy-
lated Heterocycles 2; General Procedure
At –78 °C and under argon, a solution of 2.3 M of n-BuLi in hex-
anes (0.64 mmol) was added dropwise to a solution of 4 (0.64
mmol) in anhyd THF (10 mL). After stirring for 5 min, compound
2 (0.70 mmol) in anhyd THF (5 mL) was added. The final solution
13C NMR (75 MHz, CDCl3): d = 15.0 (CH3), 28.1 (3 CH3), 55.6
(OCH3), 64.7 (CH2), 77.7 (CH2N), 85.2 (C), 92.2 (C), 97.7 (C), 99.0
Synthesis 2005, No. 1, 136–146 © Thieme Stuttgart · New York

PAPER
Synthesis of Homocarbonyltopsentine Derivatives
141
was stirred at –78 °C for 45 min. The reaction was hydrolysed by
addition of sat. aq NH4Cl solution and the mixture was extracted
with CH2Cl2 (2 × 10 mL). The combined organic phases were dried
(MgSO4) and evaporated in vacuo. The crude residue was purified
by column chromatography to afford derivative 5.
7.17–7.19 (m, 2 Harom), 7.29–7.42 (m, 3 Harom), 7.74 (d, 1 Harom,
J = 1.5 Hz), 8.14–8.23 (m, 2 Harom), 8.39–8.43 (m, 1 Harom), 9.24 (s,
1 Harom).
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3), 28.2 (3 CH3), 28.3 (3
CH3), 64.1 (CH), 65.2 (CH2), 73.9 (CH2N), 84.3 (C), 85.5 (C), 88.5
(C), 115.1 (CH), 115.5 (CH), 118.1 (C), 119.8 (CH), 120.4 (C),
122.5 (CH), 123.2 (CH), 123.6 (CH), 124.6 (CH), 125.0 (CH),
125.6 (CH), 127.6 (C), 128.4 (C), 135.3 (C), 136.1 (C), 137.8 (CH),
138.5 (C), 146.4 (C), 149.1 (C=O), 149.7 (C=O), 178.3 (C=O).
tert-Butyl 3-{5-[(1-tert-Butoxycarbonyl-1H-indol-3-yl)hy-
droxymethyl]-1-ethoxymethyl-4-iodo-1H-imidazole-2-carbon-
yl}-6-benzyloxy-1H-indole-1-carboxylate (5a)
Chromatography eluent: PE–EtOAc (85:15); yield: 61%; foam.
MS (ESI): m/z = 741 (M + H+).
IR (KBr): 3440, 1735, 1630 cm–1.
Anal. Calcd for C34H37IN4O7 (740.60): C, 55.14; H, 5.04; N, 7.57.
Found: C, 54.79; H, 4.89; N, 7.46.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, 3 H, J = 7.0 Hz, CH3), 1.75
(s, 9 H, 3 CH3), 1.79 (s, 9 H, 3 CH3), 3.65 (br q, 2 H, J = 7.0 Hz,
CH2), 4.73 (d, 1 H, J = 9.4 Hz, OH), 5.17 (s, 2 H, CH2O), 5.42 (d, 1
H, J = 10.5 Hz, CH2N), 6.33 (d, 1 H, J = 9.4 Hz, CHOH), 6.38 (d, 1
H, J = 10.5 Hz, CH2N), 7.10 (dd, 1 Harom, J = 2.2, 8.8 Hz), 7.18–
3-{5-[(1-tert-Butoxycarbonyl-1H-indol-3-yl)hydroxymethyl]-1-
ethoxymethyl-4-iodo-1H-imidazole-2-carbonyl}pyridine (5d)
Chromatography eluent: PE–EtOAc (6:4); yield: 70%; solid; mp
174–176 °C (dec.) (Et2O).
7.52 (m, 8 H, C6H5 + Harom), 7.83 (s, 1 Harom), 7.91 (d, 1 Harom
J = 2.2 Hz), 8.22 (d, 1 Harom, J = 8.3 Hz), 8.33 (d, 1 Harom, J = 8.8
,
IR (KBr): 3360, 1740, 1630 cm–1.
Hz), 9.20 (s, 1 Harom).
1H NMR (300 MHz, CDCl3): d = 1.15 (t, 3 H, J = 7.0 Hz, CH3), 1.73
(s, 9 H, 3 CH3), 3.62 (q, 2 H, J = 7.0 Hz, CH2), 4.51 (d, 1 H, J = 9.4
Hz, OH), 5.07 (d, 1 H, J = 10.9 Hz, CH2N), 6.20 (d, 1 H, J = 9.4 Hz,
CHOH), 6.32 (d, 1 H, J = 10.9 Hz, CH2N), 7.32–7.41 (m, 3 H, Harom
+ Hpyr), 7.75 (br d, 1 Hpyr, J = 7.9 Hz), 8.18–8.21 (m, 1 Harom), 8.39–
8.42 (m, 1 Harom), 8.59 (br d, 1 Hpyr, J = 4.1 Hz), 8.65 (s, 1 Hpyr), 9.19
(s, 1 Harom).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 28.0 (3 CH3), 28.2 (3
CH3), 63.9 (CH), 64.9 (CH2), 70.3 (CH2O), 73.7 (CH2N), 84.0 (C),
85.1 (C), 88.2 (C), 100.3 (CH), 114.0 (CH), 115.4 (CH), 118.0 (C),
119.7 (CH), 120.4 (C), 122.1 (C), 122.1 (CH), 123.0 (CH), 123.4
(CH), 124.8 (CH), 127.5 (2 CH), 127.6 (C), 127.9 (CH), 128.5 (2
CH), 136.0 (C), 136.2 (C), 136.6 (CH), 136.8 (C), 138.2 (C), 146.2
(C), 148.9 (C), 149.5 (C=O), 157.5 (C=O), 178.0 (C=O).
13C NMR (75 MHz, DMSO-d6): d = 14.4 (CH3), 27.5 (3 CH3), 63.2
(CH2), 64.6 (CH), 73.5 (CH2), 85.5 (C), 87.7 (C), 114.8 (CH), 117.1
(C), 122.0 (CH), 123.1 (CH), 124.4 (CH), 125.5 (CH), 127.7 (C),
133.4 (CH), 134.4 (C), 136.8 (C), 137.1 (CH), 139.3 (C), 145.2 (C),
147.2 (CH), 148.3 (CH), 148.4 (C=O), 177.2 (C=O).
MS (ESI): m/z = 847 (M + H+).
Anal. Calcd for C41H43IN4O8 (846.73): C, 58.16; H, 5.12; N, 6.62.
Found: C, 57.80; H, 4.96; N, 6.44.
tert-Butyl 3-{5-[(1-tert-Butoxycarbonyl-1H-indol-3-yl)hy-
droxymethyl]-1-ethoxymethyl-4-iodo-1H-imidazole-2-carbon-
yl}-6-methoxy-1H-indole-1-carboxylate (5b)
Chromatography eluent: PE–EtOAc (85:15); yield: 61%; solid; mp
161–163 °C (dec.) (Et2O–pentane).
MS (ESI): m/z 603 (M + H+).
Anal. Calcd for C26H27IN4O5 (602.43): C, 51.84; H, 4.52; N, 9.30.
Found: C, 51.90; H, 4.45; N, 9.15.
IR (KBr): 3410, 1730, 1620, 1530 cm–1.
3-{5-[(1-tert-Butoxycarbonyl-1H-indol-3-yl)hydroxymethyl]-1-
ethoxymethyl-4-iodo-1H-imidazole-2-carbonyl}ben-
zo[b]thiophene (5e)
Chromatography eluent: PE–EtOAc (9:1); yield: 65%; solid; mp
162–164 °C (dec.) (Et2O).
1H NMR (300 MHz, CDCl3): d = 1.18 (t, 3 H, J = 7.0 Hz, CH3), 1.70
(s, 9 H, 3 CH3), 1.75 (s, 9 H, 3 CH3), 3.60–3.65 (m, 2 H, CH2), 3.88
(s, 3 H, OCH3), 4.70 (d, 1 H, J = 10.0 Hz, OH), 5.29 (d, 1 H,
J = 10.6 Hz, CH2N), 6.27 (d, 1 H, J = 10.0 Hz, CHOH), 6.35 (d, 1
H, J = 10.6 Hz, CH2N), 6.97 (dd, 1 H, J = 2.1, 8.7 Hz, H-5), 7.12–
7.34 (m, 3 Harom), 7.75–7.77 (m, 2 Harom), 8.15 (br d, 1 Harom, J = 8.0
Hz), 8.24 (d, 1 Harom, J = 8.7 Hz), 9.11 (s, 1 Harom).
IR (KBr): 3375, 1740, 1630 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, 3 H, J = 7.0 Hz, CH3), 1.75
(s, 9 H, 3 CH3), 3.57–3.66 (m, 2 H, CH2), 4.62 (d, 1 H, J = 10.2 Hz,
OH), 5.12 (d, 1 H, J = 10.7 Hz, CH2N), 6.31 (d, 1 H, J = 10.2 Hz,
CHOH), 6.29–6.35 (d, 1 H, J = 10.7 Hz, CH2N), 7.28–7.42 (m, 4
Harom), 7.52 (dd, 1 Harom, J = 2.0, 6.8 Hz), 7.65 (d, 1 Harom, J = 1.5
Hz), 7.87 (dd, 1 Harom, J = 2.0, 6.8 Hz), 8.18 (dd, 1 Harom, J = 2.0, 6.8
Hz), 8.38 (dd, 1 Harom, J = 1.8, 6.8 Hz), 9.23 (s, 1 Harom).
13C NMR (75 MHz, CDCl3): d = 14.8 (CH3), 28.1 (3 CH3), 28.3 (3
CH3), 55.6 (OCH3), 64.0 (CH), 65.1 (CH2), 73.8 (CH2N), 84.2 (C),
85.3 (C), 88.5 (C), 99.0 (CH), 113.6 (CH), 115.5 (CH), 118.1 (C),
119.8 (CH), 120.3 (CH), 121.8 (C), 122.9 (CH), 123.1 (CH), 123.5
(CH), 124.9 (CH), 127.5 (C), 136.0 (C), 136.3 (C), 136.6 (CH),
138.3 (C), 146.3 (C), 149.1 (C), 149.6 (C=O), 158.4 (C=O), 178.2
(C=O).
13C NMR (75 MHz, DMSO-d6): d = 15.0 (CH3), 28.2 (3 CH3), 65.3
(CH2), 66.0 (CH), 73.8 (CH2N), 85.6 (C), 89.0 (C), 115.2 (CH),
118.1 (C), 122.5 (CH), 122.6 (CH), 123.2 (CH), 123.8 (CH), 124.6
(CH), 124.7 (CH), 124.8 (CH), 125.7 (CH), 128.4 (C), 135.0 (C),
135.3 (C), 136.3 (C), 137.9 (CH), 138.4 (C), 141.3 (C), 146.4 (C),
149.1 (C), 178.4 (C=O).
MS (ESI): m/z = 771 (M + H+).
Anal. Calcd for C35H39IN4O8 (770.63): C, 54.55; H, 5.10; N, 7.27.
Found: C, 54.59; H, 4.97; N, 7.37.
MS (ESI): m/z = 658 (M + H+).
tert-Butyl 3-{5-[(1-tert-Butoxycarbonyl-1H-indol-3-yl)hy-
droxymethyl]-1-ethoxymethyl-4-iodo-1H-imidazole-2-carbon-
yl}indole-1-carboxylate (5c)
Anal. Calcd for C29H28IN3O5S (657.53): C, 52.97; H, 4.29; N, 6.39.
Found: C, 53.27; H, 4.25; N, 6.50.
Chromatography eluent: PE–EtOAc (85:15); yield: 71%; foam.
IR (KBr): 3432, 1739, 1633, 1479 cm–1.
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-iodo-1H-imidazole-2-carbonyl]-6-benzyloxy-
1H-indole-1-carboxylate (6a)
According to the procedure described for 4, compound 6a was pre-
pared from 5a in 84% yield as a foam (chromatography eluent: PE–
EtOAc, 85:15).
1H NMR (300 MHz, CDCl3): d = 1.19 (t, 3 H, J = 7.0 Hz, CH3), 1.70
(s, 9 H, 3 CH3), 1.75 (s, 9 H, 3 CH3), 3.61–3.72 (m, 2 H, CH2), 4.57
(d, 1 H, J = 10.4 Hz, OH), 5.26 (d, 1 H, J = 10.7 Hz, CH2N), 6.25
(dd, 1 H, J = 1.5, 10.4 Hz, CHOH), 6.37 (d, 1 H, J = 10.7 Hz, CHN),
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142
C. Montagne et al.
PAPER
IR (KBr): 1745, 1640 cm–1.
Anal. Calcd for C34H35IN4O7 (738.59): C, 55.29; H, 4.78; N, 7.59.
Found: C, 54.96; H, 4.63; N, 7.68.
1H NMR (300 MHz, CDCl3): d = 1.05 (t, 3 H, J = 7.0 Hz, CH3), 1.72
(s, 9 H, 3 CH3), 1.75 (s, 9 H, 3 CH3), 3.57 (q, 2 H, J = 7.0 Hz, CH2),
5.17 (s, 2 H, CH2O), 6.10 (s, 2 H, CH2N), 7.13 (dd, 1 Harom, J = 2.3,
8.8 Hz), 7.31–7.51 (m, 7 H, C6H5 + Harom), 7.92 (d, 1 Harom, J = 2.3
Hz), 8.23 (dd, 1 Harom, J = 2.0, 6.5 Hz), 8.28 (s, 1 Harom), 8.36 (dd, 1
tert-Butyl 3-[1-Ethoxymethyl-4-iodo-5-(pyridine-3-carbonyl)-
1H-imidazole-2-carbonyl]indole-1-carboxylate (6d)
According to the procedure described for 4, compound 6d was pre-
pared from 5d in 82% yield as a solid; mp 168–169 °C (EtOH).
Harom, J = 2.0, 6.5 Hz), 8.40 (d, 1 Harom, J = 8.7 Hz), 9.15 (s, 1 Harom).
IR (KBr): 1745, 1657, 1628 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.8 (CH3), 28.1 (6 CH3), 65.0
(CH2), 70.4 (CH2O), 74.9 (CH2N), 85.3 (C), 85.9 (C), 87.5 (C),
100.4 (CH), 114.3 (CH), 115.3 (CH), 118.3 (C), 119.5 (C), 122.0
(C), 122.4 (CH), 123.1 (CH), 124.9 (CH), 126.1 (CH), 127.1 (C),
127.6 (2 CH), 128.0 (CH), 128.6 (2 CH), 135.9 (C), 136.4 (C),
136.7 (C), 136.8 (CH), 136.9 (C + CH), 146.3 (C), 148.8 (C), 149.0
(C=O), 157.7 (C=O), 177.9 (C=O), 181.3 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.01 (t, 3 H, J = 7.0 Hz, CH3), 1.72
(s, 9 H, 3 CH3), 3.50 (q, 2 H, J = 7.0 Hz, CH2), 6.10 (s, 2 H, CH2N),
7.37–7.45 (m, 2 Harom), 7.51 (dd, 1 Hpyr, J = 4.9, 7.9 Hz), 8.16–8.20
(m, 2 H, Harom + Hpyr), 8.45–8.49 (m, 1 Harom), 8.88 (d, 1 Hpyr, J = 4.9
Hz), 9.06 (s, 1 Hpyr), 9.20 (s, 1Harom).
13C NMR (75 MHz, CDCl3): d = 14.8 (CH3), 28.1 (3 CH3), 65.1
(CH2), 75.2 (CH2N), 85.7 (C), 90.4 (C), 115.2 (CH), 118.2 (C),
122.6 (CH), 123.9 (CH), 124.8 (CH), 125.9 (CH), 128.2 (C), 132.4
(C), 134.7 (C), 135.4 (C), 137.3 (CH), 138.2 (CH), 147.4 (C), 149.0
(C), 151.6 (CH), 154.3 (C=O), 178.0 (C=O), 186.2 (C=O).
MS (ESI): m/z = 845 (M + H+).
Anal. Calcd for C41H41IN4O8 (844.71): C, 58.30; H, 4.89; N, 6.63.
Found: C, 58.15; H, 4.95; N, 6.51.
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-iodo-1H-imidazole-2-carbonyl]-6-methoxy-
1H-indole-1-carboxylate (6b)
According to the procedure described for 4, compound 6b was pre-
pared from 5b in 99% yield as a solid; mp 157–158 °C (EtOAc–
pentane).
MS (ESI): m/z = 601 (M + H+).
Anal. Calcd for C26H25IN4O5 (600.42): C, 52.01; H, 4.20; N, 9.33.
Found: C, 52.34; H, 4.25; N, 9.21.
tert-Butyl 3-[5-(Benzo[b]thiophene-3-carbonyl)-1-ethoxymeth-
yl-4-iodo-1H-imidazole-2-carbonyl]indole-1-carboxylate (6e)
According to the procedure described for 4, compound 6e was pre-
pared from 5e in 65% yield as a solid (chromatography eluent: PE–
EtOAc, 9:1); mp 169–171 °C (dec.) (Et2O).
IR (KBr): 1740, 1630, 1530 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.01 (t, 3 H, J = 7.0 Hz, CH3), 1.70
(s, 9 H, 3 CH3), 1.73 (s, 9 H, 3 CH3), 3.53 (q, 2 H, J = 7.0 Hz, CH2),
3.91 (s, 3 H, OCH3), 6.05 (s, 2 H, CH2N), 7.02 (dd, 1 Harom, J = 2.2,
8.7 Hz), 7.40–7.49 (m, 2 Harom), 7.78 (d, 1 Harom, J = 2.2 Hz), 8.19
(d, 1 Harom, J = 7.0 Hz), 8.24 (s, 1 Harom), 8.31–8.35 (m, 2 Harom),
9.07 (s, 1 Harom).
IR (KBr): 1740, 1630 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, 3 H, J = 7.1 Hz, CH3), 1.73
(s, 9 H, 3 CH3), 3.52 (q, 2 H, J = 7.1 Hz, CH2), 6.08 (s, 2 H, CH2N),
7.38–7.48 (m, 2 Harom), 7.50–7.60 (m, 2 Harom), 7.93 (d, 1 Harom
,
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3), 28.1 (3 CH3), 28.2 (3
CH3), 55.6 (OCH3), 65.1 (CH2), 75.0 (CH2N), 85.4 (C), 86.0 (C),
87.6 (C), 99.1 (CH), 113.7 (CH), 115.3 (CH), 118.4 (C), 119.5 (C),
121.7 (C), 122.4 (CH), 123.1 (CH), 124.9 (CH), 126.1 (CH), 127.1
(C), 135.9 (C), 136.5 (C), 136.7 (C), 136.8 (CH), 137.0 (CH), 146.4
(C), 148.9 (C), 149.1 (C=O), 149.5 (C=O), 178.5 (C=O), 181.9
(C=O).
J = 7.9 Hz), 8.19–8.22 (m, 1 Harom), 8.26 (s, 1 Harom), 8.47–8.50 (m,
1 Harom), 8.66 (d, 1 Harom, J = 8.1 Hz), 9.22 (s, 1 Harom).
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3), 28.2 (3 CH3), 65.0
(CH2), 75.2 (CH2N), 85.6 (C), 88.6 (C), 115.2 (CH), 118.3 (C),
122.6 (2 CH), 124.8 (CH), 125.2 (CH), 125.8 (CH), 126.2 (CH),
126.4 (CH), 128.3 (C), 134.6 (C), 135.4 (C), 136.2 (C), 136.7 (C),
138.1 (CH), 140.4 (C), 142.8 (CH), 146.7 (C), 149.0 (C=O), 178.1
(C=O), 181.1 (C=O).
MS (ESI): m/z = 769 (M + H+).
MS (ESI): m/z = 656 (M + H+).
Anal. Calcd for C35H37IN4O8 (768.61): C, 54.69; H, 4.85; N, 7.29.
Found: C, 54.89; H, 4.66; N, 7.11.
Anal. Calcd for C29H26I2N3O5S (655.52): C, 53.14; H, 4.00; N, 6.41.
Found: C, 52.88; H, 3.90; N, 6.32.
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-iodo-1H-imidazole-2-carbonyl]indole-1-car-
boxylate (6c)
According to the procedure described for 4, compound 6c was pre-
pared from 5c in 84% yield as a solid; mp 162–164 °C (dec.)
(EtOH).
Hydrogenolysis of Iodoimidazoles 6; General Procedure
A suspension of 6 (0.20 mmol), K2CO3 (1 mmol) and 10% Pd/C (15
mg) in CH2Cl2–MeOH (12 mL, 1:1) was stirred in a stainless steel
reactor under 15 bar of H2 overnight at r.t. The catalyst was removed
by filtration and the filtrate was evaporated in vacuo. The crude res-
idue was purified by column chromatography to afford derivative 7.
IR (KBr): 1750, 1640, 1530 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.02 (t, 3 H, J = 7.0 Hz, CH3), 1.71
(s, 9 H, 3 CH3), 1.74 (s, 9 H, 3 CH3), 3.54 (q, 2 H, J = 7.0 Hz, CH2),
6.06 (s, 2 H, CH2N), 7.40–7.50 (m, 4 Harom), 8.18–8.23 (m, 2 Harom),
8.23 (s, 1 Harom), 8.33 (d, 1 Harom, J = 6.6 Hz), 8.48–8.51 (m, 1
Harom), 9.22 (s, 1 Harom).
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-1H-imidazole-2-carbonyl]-6-benzyloxy-1H-in-
dole-1-carboxylate (7a)
Chromatography eluent: PE–EtOAc (85:15); yield: 89%; solid; mp
154–156 °C (dec.) (EtOAc–pentane).
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3), 28.1 (3 CH3), 28.2 (3
CH3), 65.1 (CH2), 75.0 (CH2N), 85.5 (C), 86.0 (C), 87.5 (C), 115.1
(CH), 115.3 (CH), 118.2 (C), 119.6 (C), 122.4 (CH), 122.6 (CH),
124.7 (CH), 124.9 (CH), 125.7 (CH), 126.1 (CH), 127.1 (C), 128.3
(C), 135.3 (C), 135.9 (C), 136.8 (C), 136.9 (CH), 138.0 (CH), 146.4
(C), 148.9 (C=O), 149.0 (C=O), 178.0 (C=O), 181.4 (C=O).
IR (KBr): 1740, 1640 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14 (t, 3 H, J = 7.0 Hz, CH3), 1.72
(s, 9 H, 3 CH3), 1.73 (s, 9 H, 3 CH3), 3.64 (q, 2 H, J = 7.0 Hz, CH2),
5.16 (s, 2 H, CH2O), 6.35 (s, 2 H, CH2N), 7.13 (dd, 1 Harom, J = 2.2,
8.8 Hz), 7.31–7.50 (m, 7 H, C6H5 + Harom), 7.77 (s, 1 Himid), 7.88 (d,
1 Harom, J = 2.2 Hz), 8.20 (br d, 1 Harom, J = 7.0 Hz), 8.30 (s, 1 Harom),
8.40 (dd, 1 Harom, J = 2.0, 7.0 Hz), 8.43 (d, 1 Harom, J = 8.8 Hz), 9.03
(s, 1 Harom).
MS (ESI): m/z = 739 (M + H+).
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Synthesis of Homocarbonyltopsentine Derivatives
143
13C NMR (75 MHz, CDCl3): d = 15.1 (CH3), 28.1 (3 CH3), 28.1 (3
CH3), 64.9 (CH2), 70.3 (CH2O), 74.5 (CH2N), 85.3 (C), 85.7 (C),
100.4 (CH), 114.2 (CH), 115.2 (CH), 118.8 (C), 120.7 (C), 122.1
(C), 122.4 (CH), 123.2 (CH), 124.5 (CH), 126.0 (CH), 127.5 (2
CH), 127.8 (C), 127.9 (CH), 128.5 (2 CH), 133.2 (CH + C), 135.7
(C), 136.2 (CH), 136.3 (CH), 136.4 (C), 136.9 (C), 146.8 (C), 149.0
(C), 149.1 (C=O), 157.7 (C=O), 179.3 (C=O), 180.1 (C=O).
Himid), 8.16–8.24 (m, 2 H, Harom + Hpyr), 8.50–8.54 (m, 1 Harom), 8.88
(dd, 1 Hpyr, J = 1.7, 4.9 Hz), 9.08 (s, 1 Harom), 9.14 (d, 1 Hpyr, J = 1.7
Hz).
13C NMR (75 MHz, CDCl3): d = 15.1 (CH3), 28.2 (3 CH3), 65.0
(CH2O), 74.9 (CH2N), 85.7 (C), 115.2 (CH), 118.7 (C), 122.7 (CH),
123.7 (CH), 124.8 (CH), 125.9 (CH), 128.2 (C), 131.7 (C), 134.1
(C), 135.4 (C), 136.8 (CH), 137.9 (CH), 139.6 (CH), 147.8 (C),
149.1 (C), 150.4 (CH), 153.6 (C=O), 179.4 (C=O), 184.1 (C=O).
MS (ESI): m/z = 719 (M + H+).
Anal. Calcd for C41H42N4O8 (718.81): C, 68.51; H, 5.89; N, 7.79.
Found: C, 68.33; H, 6.01; N, 7.88.
MS (ESI): m/z = 475 (M + H+).
Anal. Calcd for C26H26N4O5 (474.52): C, 65.81; H, 5.52; N, 11.81.
Found: C, 65.99; H, 5.55; N, 11.90.
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-1H-imidazole-2-carbonyl]-6-methoxy-1H-in-
dole-1-carboxylate (7b)
Chromatography eluent: PE–EtOAc (85:15); yield: 93%; solid; mp
155–156 °C (dec.) (EtOAc–pentane).
tert-Butyl 3-[1-Ethoxymethyl-5-(1,4,5,6-tetrahydropyridine-3-
carbonyl)-1H-imidazole-2-carbonyl]indole-1-carboxylate (7f)
Yield: 20%; amorphous solid.
IR (KBr): 1750, 1630 cm–1.
IR (KBr): 1740, 1625, 1530 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 (t, 3 H, J = 7.0 Hz, CH3), 1.70
(s, 9 H, 3 CH3), 1.86–1.94 (m, 2 H, CH2), 2.56 (t, 2 H, J = 6.2 Hz,
CH2), 3.32 (br s, 2 H, CH2), 3.53 (q, 2 H, J = 7.0 Hz, CH2), 5.13 (br
s, 1 H, NH), 6.08 (s, 2 H, CH2N), 7.23 (s, 1 Himid), 7.35–7.42 (m, 2
Harom), 7.54 (d, 1 H, J = 6.6 Hz, =CH), 8.14–8.17 (m, 1 Harom), 8.48–
8.51 (m, 1 Harom), 9.05 (s, 1 Harom).
1H NMR (300 MHz, CDCl3): d = 1.11 (t, 3 H, J = 7.0 Hz, CH3), 1.71
(s, 9 H, 3 CH3), 1.72 (s, 9 H, 3 CH3), 3.61 (q, 2 H, J = 7.0 Hz, CH2),
3.91 (s, 3 H, OCH3), 6.31 (s, 2 H, CH2N), 7.03 (dd, 1 Harom, J = 2.2,
8.8 Hz), 7.38–7.48 (m, 2 Harom), 7.74 (s, 1 Himid), 7.77 (d, 1 Harom
J = 2.2 Hz), 8.19 (br d, 1 Harom, J = 7.0 Hz), 8.27 (s, 1 Harom), 8.36–
,
8.40 (m, 2 Harom), 8.97 (s, 1 Harom).
MS (ESI): m/z = 479 (M + H+).
13C NMR (75 MHz, CDCl3): d = 15.1 (CH3), 28.1 (3 CH3), 28.2 (3
CH3), 55.7 (OCH3), 65.0 (CH2), 74.6 (CH2N), 85.4 (C), 85.9 (C),
99.2 (CH), 113.7 (CH), 115.3 (CH), 118.9 (C), 120.8 (C), 121.9 (C),
122.5 (CH), 123.3 (CH), 124.7 (CH), 126.2 (CH), 127.9 (C), 133.3
(C + CH), 135.8 (C), 136.3 (2 CH), 136.5 (C), 146.9 (C), 149.1 (C),
149.3 (C=O), 158.6 (C=O), 179.5 (C=O), 180.2 (C=O).
Anal. Calcd for C26H30N4O5 (478.55): C, 65.26; H, 6.32; N, 11.71.
Found: C, 65.43; H, 6.19; N, 11.86.
tert-Butyl 3-[5-(Benzo[b]thiophene-3-carbonyl)-1-ethoxymeth-
yl-1H-imidazole-2-carbonyl]indole-1-carboxylate (7e)
Chromatography eluent: PE–EtOAc (9:1); yield: 80%; solid; mp
173-175 °C (dec.) (Et2O).
MS (ESI): m/z = 643 (M + H+).
Anal. Calcd for C35H38N4O8 (642.72): C, 65.41; H, 5.96; N, 8.72.
Found: C, 65.25; H, 6.10; N, 8.63.
IR (KBr): 1740, 1630 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (t, 3 H, J = 7.0 Hz, CH3), 1.71
(s, 9 H, 3 CH3), 3.62 (q, 2 H, J = 7.0 Hz, CH2), 6.34 (s, 2 H, CH2N),
7.40–7.57 (m, 4 Harom), 7.69 (s, 1 Himid), 7.93 (d, 1 Harom, J = 8.1
Hz), 8.17–8.20 (m, 1 Harom), 8.29 (s, 1 Harom), 8.51–8.55 (m, 1
Harom), 8.60 (d, 1 Harom, J = 7.0 Hz), 9.11 (s, 1 Harom).
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-1H-imidazole-2-carbonyl]indole-1-carboxy-
late (7c)
Chromatography eluent: PE–EtOAc (85:15); yield: 85%; solid; mp
162–163 °C (dec.) (EtOAc–PE).
13C NMR (75 MHz, DMSO-d6): d = 15.2 (CH3), 28.2 (3 CH3), 65.1
(CH2), 74.8 (CH2N), 85.7 (C), 115.2 (CH), 118.8 (C), 122.6 (CH),
122.8 (CH), 124.8 (CH), 125.1 (CH), 125.8 (CH), 126.0 (CH),
126.1 (CH), 128.4 (C), 133.5 (C), 135.4 (C), 135.9 (C), 137.0 (C),
137.6 (CH), 137.7 (CH), 138.2 (CH), 140.2 (C), 147.3 (C), 149.2
(C=O), 179.5 (C=O), 180.0 (C=O).
IR (KBr): 1750, 1740, 1640, 1530 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (t, 3 H, J = 7.0 Hz, CH3), 1.72
(s, 18 H, 6 CH3), 3.62 (q, 2 H, J = 7.0 Hz, CH2), 6.33 (s, 2 H, CH2N),
7.40–7.50 (m, 4 Harom), 7.75 (s, 1 Himid), 8.18–8.21 (m, 2 Harom), 8.21
(s, 1 Harom), 8.36–8.39 (m, 1 Harom), 8.52–8.55 (m, 1 Harom), 9.12 (s,
1 Harom).
MS (ESI): m/z = 530 (M + H+).
13C NMR (75 MHz, CDCl3): d = 15.1 (CH3), 28.2 (6 CH3), 65.0
(CH2), 74.7 (CH2N), 85.6 (C), 85.8 (C), 115.2 (CH), 115.3 (CH),
118.8 (C), 120.8 (C), 122.5 (CH), 122.8 (CH), 124.7 (2 CH), 125.7
(CH), 126.2 (CH), 127.9 (C), 128.4 (C), 133.3 (CH), 133.4 (C),
135.4 (C), 135.8 (C), 136.3 (CH), 137.6 (CH), 146.9 (C), 149.1
(C=O), 149.2 (C=O), 179.5 (C=O), 180.2 (C=O).
Anal. Calcd for C29H27N3O5S (529.62): C, 65.77; H, 5.14; N, 7.93.
Found: C, 65.98; H, 4.97; N, 8.06.
Boc Deprotection of 7; General Procedure
A solution of 7 (0.17 mmol), and aq 1 N NaOH (2 mL) in 1,4-diox-
ane (4 mL) was stirred at 70 °C for 30 min. After cooling, the solu-
tion was neutralised by aq 1 N HCl (pH 6–7) and extracted with
CH2Cl2 (2 × 5 mL). The combined organic phases were dried
(MgSO4) and evaporated in vacuo. Product 8 was isolated either by
crystallisation or by column chromatography.
MS (ESI): m/z = 613 (M + H+).
Anal. Calcd for C34H36N4O7 (612.69): C, 66.75; H, 5.92; N, 9.14.
Found: C, 66.40; H, 5.76; N, 8.99.
[1-Ethoxymethyl-5-(1H-indole-3-carbonyl)-1H-imidazol-2-
yl](6-benzyloxy-1H-indol-3-yl)methanone (8a)
Yield: 85%; solid; mp >210 °C (dec.) (EtOAc–pentane).
tert-Butyl 3-[1-Ethoxymethyl-5-(pyridine-3-carbonyl)-1H-imi-
dazole-2-carbonyl]indole-1-carboxylate (7d)
Chromatography eluent: PE–EtOAc (85:15); yield: 55%; solid; mp
157–159 °C (dec.) (EtOH).
IR (KBr): 3415, 3285, 1612 cm–1.
IR (KBr): 1732, 1655, 1630 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 (t, 3 H, J = 7.0 Hz, CH3), 3.64
(q, 2 H, J = 7.0 Hz, CH2), 4.98 (s, 2 H, CH2O), 6.31 (s, 2 H, CH2N),
6.83 (s, 1 Harom), 7.07 (dd, 1 Harom, J = 2.1, 8.7 Hz), 7.28–7.39 (m, 8
1H NMR (300 MHz, CDCl3): d = 1.13 (t, 3 H, J = 7.0 Hz, CH3), 1.71
(s, 9 H, 3 CH3), 3.61 (q, 2 H, J = 7.0 Hz, CH2), 6.34 (s, 2 H, CH2N),
7.40–7.44 (m, 2 Harom), 7.50 (dd, 1 Hpyr, J = 4.9, 7.9 Hz), 7.66 (s, 1
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144
C. Montagne et al.
PAPER
H, C6H5 + Harom), 7.44 (s, 1 Harom), 7.67 (s, 1 Himid), 8.42–8.45 (m, 3
arom), 8.97 (s, 1 H, NH), 9.00 (s, 1 H NH).
140.2 (CH), 149.7 (C), 150.9 (CH), 154.2 (CH), 179.5 (C=O), 185.0
(C=O).
H
13C NMR (75 MHz, DMSO-d6): d = 14.8 (CH3), 63.6 (CH2), 69.5
(CH2O), 73.7 (CH2N), 97.1 (CH), 112.4 (CH), 112.6 (CH), 115.2
(C), 116.5 (C), 120.5 (C), 121.4 (CH), 122.1 (CH), 122.2 (CH),
123.4 (CH), 126.0 (C), 127.6 (2 CH), 127.7 (CH), 128.4 (2 CH),
133.2 (C), 134.5 (CH), 135.8 (CH), 136.9 (C), 137.2 (C), 137.3 (C),
137.7 (CH), 146.8 (C), 155.7 (C), 178.3 (C=O), 179.3 (C=O).
MS (ESI): m/z = 375 (M + H+).
Anal. Calcd for C21H18N4O3 (374.40): C, 67.37; H, 4.85; N, 14.96.
Found: C, 66.98; H, 5.00; N, 15.10.
[5-(Benzo[b]thiophene-3-carbonyl)-1-ethoxymethyl-1H-imida-
zol-2-yl](1H-indol-3-yl)methanone (8e)
Chromatography eluent: PE–EtOAc (6:4); yield: 80%; foam.
MS (ESI): m/z = 519 (M + H+).
IR (KBr): 3375, 1630 cm–1.
Anal. Calcd for C31H26N4O4 (518.58): C, 71.80; H, 5.05; N, 10.80.
Found: C, 71.98; H, 4.93; N, 10.67.
1H NMR (300 MHz, CDCl3): d = 1.11 (t, 3 H, J = 7.0 Hz, CH3), 3.63
(q, 2 H, J = 7.0 Hz, CH2), 6.37 (s, 2 H, CH2N), 7.32–7.56 (m, 5
Harom), 7.66 (s, 1 Himid), 7.94 (br d, 1 Harom, J = 7.4 Hz), 8.26 (s, 1
Harom), 8.57–8.61 (m, 2 Harom), 8.73 (s, 1 H, NH), 8.78 (d, 1 Harom
J = 3.0 Hz).
[1-Ethoxymethyl-5-(1H-indole-3-carbonyl)-1H-imidazol-2-
yl](6-methoxy-1H-indol-3-yl)methanone (8b)
Yield: 89%; solid; mp 169–171 °C (dec.) (EtOAc).
,
IR (KBr): 3340, 1615, 1510 cm–1.
13C NMR (75 MHz, CDCl3): d = 15.1 (CH3), 65.1 (CH2), 74.7
(CH2N), 111.8 (CH), 116.7 (C), 122.6 (2 CH), 123.3 (CH), 124.1
(CH), 125.0 (CH), 126.0 (CH), 126.1 (CH), 126.6 (C), 133.0 (C),
135.8 (C), 136.3 (C), 137.0 (C), 137.5 (CH), 137.6 (CH), 138.0
(CH), 140.2 (C), 148.2 (C), 178.8 (C=O), 179.9 (C=O).
1H NMR (300 MHz, DMSO-d6): d = 0.91 (t, 3 H, J = 7.0 Hz, CH3),
3.40 (q, 2 H, J = 7.0 Hz, CH2), 3.82 (s, 3 H, OCH3), 6.15 (s, 2 H,
CH2N), 6.91 (dd, 1 Harom, J = 2.1, 8.7 Hz), 7.04 (d, 1 Harom, J = 2.1
Hz), 7.23–7.32 (m, 2 Harom), 7.54 (br d, 1 Harom, J = 7.0 Hz), 7.77 (s,
1 Himid), 8.19 (d, 1 Harom, J = 8.7 Hz), 8.25–8.29 (m, 2 Harom), 8.62
(s, 1 Harom), 12.05 (br s, 1 H, NH), 12.22 (br s, 1 H, NH).
MS (ESI): m/z = 430 (M + H+).
Anal. Calcd for C24H19N3O3S (429.50): C, 67.12; H, 4.46; N, 9.78.
Found: C, 66.80; H, 4.33; N, 9.75.
13C NMR (75 MHz, DMSO-d6): d = 14.9 (CH3), 55.3 (OCH3), 63.7
(CH2), 73.7 (CH2N), 95.7 (CH), 112.0 (CH), 112.4 (CH), 115.3 (C),
116.5 (C), 120.3 (C), 121.4 (CH), 122.2 (2 CH), 123.5 (CH), 126.0
(CH), 133.2 (C), 134.5 (CH), 135.9 (CH), 136.9 (C), 137.4 (C),
137.6 (CH), 146.9 (C), 156.7 (C), 178.3 (C=O), 179.4 (C=O).
EOM Deprotection of Imidazoles 8; General Procedure
A solution of 8 (0.11 mmol) and aq 1 N HCl (1 mL) in 1,4-dioxane
(2 mL) was stirred at 70 °C for 30 min. After cooling, the solution
was neutralised by sat. aq NaHCO3 and extracted with CH2Cl2
(2 × 5 mL). The combined organic phases were dried (MgSO4) and
evaporated in vacuo. The crude residue was recrystallised (or
washed) to afford 9.
MS (ESI): m/z = 443 (M + H+).
Anal. Calcd for C25H22N4O4 (442.48): C, 67.86; H, 5.01; N, 12.66.
Found: C, 67.99; H, 4.95; N, 12.80.
[1-Ethoxymethyl-5-(1H-indole-3-carbonyl)-1H-imidazol-2-
yl](1H-indol-3-yl)methanone (8c)
Yield: 89%; solid; mp 209–210 °C (CHCl3).
[5-(1H-Indole-3-carbonyl)-1H-imidazol-2-yl](6-benzyloxy-1H-
indol-3-yl)methanone (9a)
Yield: 83%; solid; mp >210 °C (EtOH).
IR (KBr): 3400, 1610, 1520 cm–1.
IR (KBr): 3395, 3340, 1605, 1575 cm–1.
1H NMR (300 MHz, CD3OD): d = 0.99 (t, 3 H, J = 7.0 Hz, CH3),
3.50 (q, 2 H, J = 7.0 Hz, CH2), 6.20 (s, 2 H, CH2N), 7.20–7.32 (m,
4 Harom), 7.49–7.53 (m, 2 Harom), 7.67 (s, 1 Himid), 8.12 (s, 1 Harom),
8.31–8.34 (m, 1 Harom), 8.38–8.42 (m, 1 Harom), 8.52 (s, 1 Harom).
1H NMR (300 MHz, DMSO-d6): d = 5.18 (s, 2 H, CH2O), 7.00 (dd,
1 H, J = 2.2, 8.7 Hz, H-5), 7.14 (d, 1 H, J = 1.9 Hz, H-7), 7.20–7.56
(m, 8 H, C6H5 + Harom), 8.01 (d, 1 Himid, J = 1.9 Hz), 8.24 (d, 1 Harom
,
J = 8.7 Hz), 8.37–8.40 (m, 1 Harom), 8.96 (br d, 1 Harom, J = 2.5 Hz),
9.01 (d, 1 Harom, J = 3.0 Hz), 11.99 (br s, 2 H, NH), 13.67 (s, 1 H,
NH).
13C NMR (75 MHz, DMSO-d6): d = 14.8 (CH3), 63.7 (CH2), 73.8
(CH2N), 112.4 (CH), 112.5 (CH), 115.2 (C), 116.6 (C), 121.4 (CH),
121.6 (CH), 122.2 (CH), 122.4 (CH), 123.4 (CH), 123.5 (CH),
126.0 (C), 126.4 (C), 133.3 (C), 134.5 (CH), 135.8 (CH), 136.4 (C),
136.9 (C), 138.4 (CH), 146.9 (C), 178.5(C=O), 179.4 (C=O).
13C NMR (75 MHz, DMSO-d6): d = 69.5 (CH2O), 96.9 (CH), 112.1
(CH), 112.5 (CH), 113.5 (C), 114.9 (C), 120.6 (C), 121.7 (CH),
121.8 (CH), 122.2 (CH), 122.9 (CH), 126.7 (C), 127.6 (2 CH),
127.8 (CH), 128.4 (2 CH), 135.5 (CH), 136.2 (C), 136.3 (2 CH),
137.1 (C), 137.3 (C), 155.6 (C), 176.3 (C=O), 181.6 (C=O).
MS (ESI): m/z = 413 (M + H+).
Anal. Calcd for C24H20N4O3 (412.45): C, 68.89; H, 4.89; N, 13.58.
Found: C, 68.98; H, 5.01; N, 13.77.
MS (ESI): m/z = 461 (M + H+).
Anal. Calcd for C28H20N4O3 (460.50): C, 73.03; H, 4.38; N, 12.17.
Found: C, 72.74; H, 4.19; N, 12.00.
1-Ethoxymethyl-5-(pyridine-3-carbonyl)-1H-imidazol-2-
yl](1H-indol-3-yl)methanone (8d)
Yield: 97%; solid; mp 170–172 °C (EtOH).
[5-(1H-Indole-3-carbonyl)-1H-imidazol-2-yl](6-methoxy-1H-
indol-3-yl)methanone (9b)
Yield: 85%; solid; mp >210 °C (EtOAc–pentane).
IR (KBr): 1650, 1610 cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.01 (t, 3 H, J = 7.0 Hz, CH3),
3.54 (q, 2 H, J = 7.0 Hz, CH2), 6.33 (s, 2 H, CH2N), 7.28–7.34 (m,
2 Harom), 7.57–7.64 (m, 2 H, Harom + Hpyr), 7.73 (s, 1 Himid), 8.27–
IR (KBr): 3205, 1592, 1510 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.82 (s, 3 H, OCH3), 6.91 (d,
1 Harom, J = 8.7 Hz), 7.07 (s, 1 Harom), 7.23–7.28 (m, 2 Harom), 7.54
(d, 1 Harom, J = 7.0 Hz), 8.01 (s, 1 Himid), 8.23 (d, 1 Harom, J = 8.7
Hz), 8.38 (d, 1 Harom, J = 8.0 Hz), 8.96–9.01 (m, 2 Harom), 11.98 (s,
2 H, NH), 13.67 (s, 1 H, NH).
8.30 (m, 1 Hpyr), 8.49–8.51 (m, 1 Harom), 8.86–8.88 (m, 2 H, Harom
pyr), 9.08 (br s, 1 Hpyr).
+
H
13C NMR (75 MHz, acetone-d6): d = 15.3 (CH3), 64.9 (CH2O), 75.3
(CH2N), 113.1 (CH), 116.9 (C), 122.9 (CH), 123.4 (CH), 124.5 (2
CH), 127.7 (C), 132.2 (C), 137.4 (CH), 137.6 (C), 139.3 (CH + C),
13C NMR (75 MHz, DMSO-d6): d = 55.3 (CH3), 95.5 (CH), 111.9
(CH), 112.2 (CH), 113.5 (C), 114.8 (C), 120.4 (C), 121.7 (CH),
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Synthesis of Homocarbonyltopsentine Derivatives
145
121.8 (CH), 122.2 (CH), 122.9 (CH), 124.3 (CH), 126.7 (C), 135.7
(CH), 136.2 (CH), 137.3 (C), 143.3 (C), 145.5 (C), 156.6 (2 C),
176.4 (C=O), 181.6 (C=O).
[5-(1H-Indole-3-carbonyl)-1H-imidazol-2-yl](6-hydroxy-1H-
indol-3-yl)methanone (Ia)
A suspension of 9a (46 mg, 0.10 mmol), HCO2NH4 (63 mg, 1.00
mmol) and 10% Pd/C (5 mg) in EtOH (5 mL) was refluxed for 1 h.
The catalyst was removed by filtration and the filtrate was evaporat-
ed in vacuo. The crude residue was washed with hot EtOAc and fil-
tered to afford Ia (34 mg, 91%) as a yellow solid; mp >210 °C
(purified by washing with hot EtOAc).
MS (ESI): m/z = 385 (M + H+).
Anal. Calcd for C22H16N4O3 (384.40): C, 68.74; H, 4.20; N, 14.58.
Found: C, 68.86; H, 4.02; N, 14.68.
[5-(1H-Indole-3-carbonyl)-1H-imidazol-2-yl](1H-indol-3-
yl)methanone (9c)
Yield: 90%; solid; mp >210 °C (purified by washing with hot
MeOH).
IR (KBr): 3380, 3200, 1592, 1572, 1525 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.78 (dd, 1 Harom, J = 1.7, 8.6
Hz), 6.92 (br s, 1 Harom), 7.20–7.28 (m, 2 Harom), 7.53–7.56 (m, 1
Harom) 8.01 (s, 1 Himid), 8.15 (d, 1 Harom, J = 8.6 Hz), 8.38–8.41 (m,
1 Harom), 8.96 (br s, 2 Harom), 9.33 (s, 1 H, OH), 11.84 (s, 1 H, NH),
11.99 (s, 1 H, NH), 13.63 (s, 1 H, NH).
IR (KBr): 3198, 1609, 1590, 1512 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.22–7.30 (m, 4 Harom), 7.53–
7.59 (m, 2 Harom), 8.02 (s, 1 Himid), 8.37–8.40 (m, 2 Harom), 8.97 (s,
1 Harom), 9.14 (s, 1 Harom), 12.00 (s, 1 H, NH), 12.21 (s, 1 H, NH),
13.70 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 97.6 (CH), 112.2 (CH), 112.3
(CH), 113.6 (C), 114.9 (C), 119.4 (C), 121.7 (CH), 121.8 (CH),
122.1 (CH), 122.9 (CH), 124.2 (CH), 126.8 (C), 135.7 (CH), 135.9
(CH), 136.2 (C), 137.6 (C), 143.3 (C), 145.6 (C), 154.4 (C), 176.3
(C=O), 181.6 (C=O).
13C NMR (75 MHz, DMSO-d6): d = 112.2 (CH), 112.5 (CH), 113.4
(C), 114.9 (C), 121.6 (CH), 121.7 (2 CH), 122.3 (CH), 122.9 (CH),
123.2 (CH), 124.3 (CH), 126.5 (C), 126.7 (C), 135.7 (CH), 136.2
(C), 136.3 (C), 137.1 (CH), 143.3 (C), 145.5 (C), 176.5 (C=O),
181.6 (C=O).
MS (ESI): m/z = 371 (M + H+).
Anal. Calcd for C21H14N4O3 (370.37): C, 68.10; H, 3.81; N, 15.13.
Found: C, 67.90; H, 3.87; N, 15.23.
MS (ESI): m/z = 355 (M + H+).
Anal. Calcd for C21H14N4O2 (354.37): C, 71.18; H, 3.98; N, 15.81.
Found: C, 70.93; H, 4.12; N, 15.77.
[5-(1H-Indole-3-carbonyl)-4-iodo-1H-imidazol-2-yl](1H-indol-
3-yl)methanone (10)
Compound 10 was prepared in 56% overall yield from 6c by two
successive deprotection reactions; mp >210 °C (purified by wash-
ing with MeOH).
(1H-Indol-3-yl)[5-(pyridine-3-carbonyl)-1H-imidazol-2-
yl]methanone (9d)
Yield: 96%; solid; mp >210 °C (dioxane–H2O).
IR (KBr): 3390, 3200, 1610, 1590, 1510 cm–1.
IR (KBr): 3280, 1610 cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.25–7.31 (m, 4 Harom), 7.53–
7.60 (m, 2 Harom), 8.45–8.55 (m, 2 Harom), 8.97 (s, 1 Harom), 9.27 (s,
1 Harom), 11.01 (s, 1 H, NH), 11.22 (s, 1 H, NH), 13.09 (s, 1 H, NH).
1H NMR (300 MHz, DMSO-d6): d = 7.24–7.26 (m, 2 Harom), 7.51–
7.53 (m, 1 Harom), 7.57–7.61 (dd, 1 Hpyr, J = 4.9, 7.9 Hz), 8.10 (s, 1
Himid), 8.42–8.46 (m, 1 Harom), 8.55 (d, 1 Hpyr, J = 7.5 Hz), 8.79 (br
13C NMR (75 MHz, DMSO-d6): d = 90.2 (C), 112.2 (CH), 112.5
(CH), 113.1 (C), 115.1 (C), 121.5 (CH), 121.7 (CH), 121.8 (CH),
122.3 (CH), 122.9 (CH), 123.3 (CH), 126.5 (2 C), 126.7 (C), 136.1
(C), 136.4 (CH + C), 136.9 (CH), 142.5 (C), 175.7 (C=O), 181.6
(C=O).
s, 1 Harom), 9.17 (s, 1 Hpyr), 9.44 (br s, 1 Hpyr), 12.13 (s, 1 H, NH),
14.10 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 112.4 (CH), 113.6 (C), 121.7
(CH), 122.0 (CH), 123.0 (CH), 123.4 (CH + C), 126.7 (C), 134.2
(C), 136.2 (C), 137.1 (CH), 137.4 (CH), 149.1 (C), 150.6 (CH),
152.0 (CH), 185.6 (2 C=O).
HRMS (ESI): m/z = 481 (M + H+).
MS (EI): m/z = 316 (M+);
Anal. Calcd for C21H13IN4O2 (480.27): C, 52.52; H, 2.73; N, 11.67.
Found: C, 52.53; H, 2.85; N, 11.79.
Anal. Calcd for C18H12N4O2 (316.32): C, 68.35; H, 3.82; N, 17.71.
Found: C, 68.01; H, 3.90; N, 17.66.
Suzuki Reaction of 6c with Arylboronic Acids; General Proce-
dure
[5-(Benzo[b]thiophene-3-carbonyl)-1H-imidazol-2-yl](1-indol-
3-yl)methanone (9e)
Chromatography eluent: EtOAc; yield: 88%; solid; mp >210 °C
(Et2O).
To a stirred solution of 6c (131 mg, 0.18 mmol) in anhyd toluene (5
mL) was added freshly prepared Pd(PPh3)4 (12 mg, 6% mol). The
solution was stirred for 30 min at r.t. The appropriate arylboronic
acid (0.27 mmol) diluted with EtOH (2 mL) was then added, fol-
lowed immediately by sat. aq NaHCO3 solution (2 mL). The hetero-
geneous solution was stirred at 80 °C for t h. The Pd catalyst was
removed by filtration. Brine was then added, the two layers were
separated and the aqueous phase was extracted with EtOAc (3 × 5
mL). The combined organic extracts were dried (MgSO4) and evap-
orated in vacuo. The crude residue was purified by column chroma-
tography to give the desired compound 11.
IR (KBr): 3375, 1740, 1630 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.25–7.31 (m, 2 Harom), 7.47–
7.58 (m, 3 Harom), 8.14 (d, 1 Harom, J = 7.2 Hz), 8.20 (s, 1 Himid),
8.37–8.40 (m, 1 Harom), 8.64 (br d, 1 Harom, J = 7.8 Hz), 9.18 (s, 1
Harom), 9.49 (s, 1 Harom), 12.2 (s, 1 H, NH), 13.9 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 112.5 (CH), 113.2 (C), 121.5
(CH), 122.3 (CH), 122.9 (CH), 123.2 (CH), 124.6 (CH), 125.3
(CH), 125.5 (CH), 126.5 (C), 126.6 (CH), 133.2 (C), 136.3 (C),
137.4 (C), 137.6 (CH), 139.2 (C), 140.8 (CH), 142.1 (C), 146.1 (C),
176.2 (C=O), 181.4 (C=O).
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-phenyl-1H-imidazole-2-carbonyl]indole-1-
carboxylate (11a)
t = 1.5 h; chromatography eluent: PE–EtOAc (9:1); yield: 92%;
amorphous solid.
MS (ESI): m/z = 372 (M + H+).
Anal. Calcd for C21H13N3O2S (371.42): C, 67.91; H, 3.53; N, 11.31.
Found: C, 68.27; H, 3.44; N, 11.15.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, 3 H, J = 7.0 Hz, CH3), 1.56
(s, 9 H, 3 CH3), 1.74 (s, 9 H, 3 CH3), 3.54 (q, 2 H, J = 7.0 Hz, CH2),
6.16 (s, 2 H, CH2N), 7.20–23 (m, 3 H, C6H5), 7.40–7.43 (m, 4
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C. Montagne et al.
PAPER
Harom), 7.60–7.63 (m, 2 H, C6H5), 7.73 (s, 1 Harom), 8.08–8.11 (m, 1
arom), 8.24–8.26 (m, 1 Harom), 8.43–8.46 (m, 1 Harom), 8.53–8.56
(m, 1 Harom), 9.54 (s, 1 Harom).
7.91 (s, 1 Himid), 8.05–8.08 (m, 1 Harom), 8.18–8.21 (m, 1 Harom),
8.36–8.39 (m, 1 Harom), 8.54–8.57 (m, 1 Harom), 9.36 (s, 1 Harom).
H
13C NMR (75 MHz, DMSO-d6): d = 14.5 (CH3), 27.0 (3 CH3), 27.4
(6 CH3), 63.7 (CH2), 73.9 (CH2N), 83.3 (C), 84.4 (C), 84.6 (C),
110.1 (CH), 114.5 (2 CH), 116.2 (CH), 117.6 (C), 118.8 (C), 121.9
(CH), 122.2 (CH), 122.3 (CH), 123.8 (CH), 123.9 (CH), 124.9
(CH), 125.1 (CH), 126.1 (C), 126.9 (C), 127.9 (C), 130.5 (C), 134.2
(CH), 134.5 (C), 134.6 (C), 136.6 (C), 137.3 (CH), 142.9 (C), 147.6
(C), 147.8 (C), 148.1 (C), 177.9 (C=O), 180.2 (C=O).
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3), 28.0 (3 CH3), 28.2 (3
CH3), 64.8 (CH2), 74.9 (CH2N), 85.2 (C), 85.5 (C), 115.1 (2 CH),
118.6 (C), 120.0 (C), 122.5 (CH), 122.7 (CH), 124.7 (CH), 124.8
(CH), 125.6 (CH), 126.0 (CH), 127.3 (C), 128.0 (CH), 128.4 (2
CH), 128.5 (2 CH), 130.1 (C), 133.2 (C), 135.4 (C), 135.7 (C),
136.3 (CH), 138.0 (CH), 142.9 (C), 144.0 (C), 148.5 (C), 149.1 (C),
179.1 (C=O), 183.1 (C=O).
MS (ESI): m/z = 778 (M + H+).
MS (ESI): m/z = 689 (M + H+).
Anal. Calcd for C43H47N5O9 (777.88): C, 66.40; H, 6.09; N, 9.00.
Found: C, 66.75; H, 5.95; N, 8.88.
Anal. Calcd for C40H40N4O7 (688.79): C, 69.75; H, 5.85; N, 8.13.
Found: C, 69.66; H, 5.90; N, 8.04.
[5-(1H-Indole-3-carbonyl)-4-phenyl-1H-imidazol-2-yl](1H-in-
dol-3-yl)methanone (12)
Compound 12 was prepared in 83% overall yield from 11a by two
successive deprotection reactions; pp 144–146 °C (dec.).
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-(2-thienyl)-1H-imidazole-2-carbonyl]indole-
1-carboxylate (11b)
t = 15 h; chromatography eluent: PE–EtOAc (9:1); yield: 95%; sol-
id; mp 142–144 °C (dec.).
IR (KBr): 3200, 1701, 1595, 1509 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.21–7.30 (m, 4 H, C6H5 +
Harom), 7.43–7.58 (m, 5 Harom), 7.78 (br d, 2 H, J = 6.0 Hz, C6H5),
8.30 (d, 1 Harom, J = 7.9 Hz), 8.39–8.41 (m, 1 Harom), 8.57 (s, 1
Harom), 9.09 (s, 1 Harom), 11.96 (s, 1 H, NH), 12.12 (s, 1 H, NH),
13.81 (s, 1 H, NH).
1H NMR (300 MHz, CDCl3): d = 1.01 (t, 3 H, J = 7.0 Hz, CH3), 1.61
(s, 9 H, 3 CH3), 1.75 (s, 9 H, 3 CH3), 3.54 (q, 2 H, J = 7.0 Hz, CH2),
6.10 (s, 2 H, CH2N), 6.85 (dd, 1 Hthienyl, J = 3.6, 5.1 Hz), 7.04 (dd,
1 Hthienyl, J = 1.0, 3.6 Hz), 7.22 (dd, 1 Hthienyl, J = 1.0, 5.0 Hz), 7.40–
7.45 (m, 4 Harom), 7.96 (s, 1 Harom), 8.13–8.17 (m, 1 Harom), 8.25–
8.28 (m, 1 Harom), 8.40–8.43 (m, 1 Harom), 8.53–8.56 (m, 1 Harom),
9.50 (s, 1 Harom).
13C NMR (75 MHz, DMSO-d6): d = 112.2 (CH), 112.4 (CH), 113.6
(C), 115.8 (C), 121.6 (CH), 121.7 (CH), 121.8 (CH), 122.2 (CH),
122.8 (CH), 123.2 (CH), 126.5 (C), 126.6 (C), 128.0 (CH), 129.2
(C), 129.3 (CH), 134.2 (CH), 136.2 (C), 136.3 (C), 136.5 (C), 136.6
(CH), 137.0 (CH), 138.3 (C), 144.4 (C), 176.4 (C=O), 183.6 (C=O).
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3), 28.1 (3 CH3), 28.2 (3
CH3), 64.9 (CH2), 75.2 (CH2N), 85.3 (C), 85.8 (C), 115.2 (CH),
115.3 (CH), 118.5 (C), 120.2 (C), 122.5 (CH), 122.7 (CH), 124.7
(CH), 124.9 (CH), 125.7 (CH), 125.9 (CH), 126.1 (CH), 126.5
(CH), 127.2 (C), 127.8 (CH), 128.5 (C), 129.1 (C), 135.5 (C), 135.9
(C+CH), 136.0 (C), 137.0 (C), 138.1 (CH), 143.5 (C), 148.7 (C),
149.1 (C), 178.8 (C=O), 182.7 (C=O).
MS (ESI): m/z = 431 (M + H+).
Anal. Calcd for C27H18N4O2 (430.47): C, 75.34; H, 4.21; N, 13.02.
Found: C, 75.03; H, 4.09; N, 12.88.
MS (ESI): m/z = 695 (M + H+).
Acknowledgement
Anal. Calcd for C38H38N4O7S (694.81): C, 65.59; H, 5.51; N, 8.06.
Found: C, 65.65; H, 5.46; N, 7.95.
This research work was supported by a grant from the Ministère de
la Jeunesse, de l’Education Nationale et de la Recherche to C.M.
tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-(2-furyl)-1H-imidazole-2-carbonyl]indole-1-
carboxylate (11c)
References
t = 48 h; chromatography eluent: PE–EtOAc (9:1); yield: 96%;
amorphous solid.
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Prod. 2000, 63, 447. (b) Faulkner, D. J. Nat. Prod. Rep.
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(4) Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans. 1 1983,
735.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, 3 H, J = 7.0 Hz, CH3), 1.62
(s, 9 H, 3 CH3), 1.74 (s, 9 H, 3 CH3), 3.53 (q, 2 H, J = 7.0 Hz, CH2),
6.09 (s, 2 H, CH2N), 6.35 (dd, 1 Hfuryl, J = 1.7, 3.2 Hz), 6.66 (d, 1
Hfuryl, J = 3.2 Hz), 7.21 (br s, 1 Hfuryl), 7.39–7.44 (m, 4 Harom), 7.92
(s, 1 Harom), 8.14–8.17 (m, 1 Harom), 8.22–8.25 (m, 1 Harom), 8.41–
8.44 (m, 1 Harom), 8.51–8.54 (m, 1 Harom), 9.42 (s, 1 Harom).
(5) Kimura, R.; Nagano, T.; Kinoshita, H. Bull. Chem. Soc. Jpn.
2002, 75, 2517.
MS (ESI): m/z = 679 (M + H+).
Anal. Calcd for C38H38N4O8 (678.75): C, 67.24; H, 5.64; N, 8.25.
Found: C, 66.99; H, 5.77; N, 8.30.
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tert-Butyl 3-[5-(1-tert-Butoxycarbonyl-1H-indole-3-carbonyl)-
1-ethoxymethyl-4-(2-(1-tert-butoxycarbonyl)pyrrolyl)-1H-imi-
dazole-2-carbonyl]indole-1-carboxylate (11d)
t = 4 h; chromatography eluent: PE–EtOAc (85:15); yield: 89%;
solid; mp 114–116 °C (dec.) (EtOH).
1H NMR (300 MHz, CDCl3): d = 1.05 (t, 3 H, J = 7.0 Hz, CH3), 1.33
(s, 9 H, 3 CH3), 1.66 (s, 9 H, 3 CH3), 1.70 (s, 9 H, 3 CH3), 3.56 (q,
2 H, J = 7.0 Hz, CH2), 6.10–6.12 (m, 1 Hpyr), 6.29 (s, 2 H, CH2N),
6.45–6.47 (m, 1 Hpyr), 7.10–7.11 (m, 1 Hpyr), 7.35–7.42 (m, 4 Harom),
(10) Young, E. H. P. J. Chem. Soc. 1958, 3493.
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Synthesis 2005, No. 1, 136–146 © Thieme Stuttgart · New York