Towards the syntheses of N-H and N-alkylated derivatives of meridianins

Article abstract of DOI:10.1002/jhet.5570440407

(Chemical Equation Presented) Novel N-H and N-alkylated derivatives of meridianins have been synthesized as potential antitumor agents by a two-step conversion of N-tosyl-3-acetylindoles or N-alkyl-3-acetylindoles to the corresponding enaminones using DMF-DMA, with or without added pyrrolidine. Further cyclization with guanidine gave the corresponding 2-aminopyrimidines. The structures of the compounds, thus obtained, were proved by ¹H and ¹³C NMR spectroscopy, NOE experiments and X-ray analysis.

Full text of DOI:10.1002/jhet.5570440407

Jul-Aug 2007
793
Towards the Syntheses of N-H and N-Alkylated
Derivatives of Meridianins
Gaëlle Simon*, Hélène Couthon-Gourves, Jean-Pierre Haelters, Bernard Corbel*a,
Nelly Kervarec, François Michaud b and Laurent Meijer c
a Laboratoire de Chimie Hétéro-Organique, U.F.R. Sciences et Techniques, 6 Av. V. Le Gorgeu – CS 93837 -
29238 Brest Cedex 3, France. Tel.: (33) 2 98 01 61 60; fax.: (33) 2 98 01 67 04; e-mail: gaelle.simon@univ-
brest.fr, bernard.corbel@univ-brest.fr.
b Services RMN-RPE, RX, U.F.R. Sciences et Techniques, 6 Av. V. Le Gorgeu – CS 93837 - 29238 Brest
Cedex 3, France.
c CNRS, Cell Cycle Group, Station Biologique, BP74, 29682 Roscoff Cedex, France.
Received July 3, 2006
R''
H2N
N
N
O
O
R''
N
R
R
R
R
N
H
N
N
N
R'
R'
R'
Novel N-H and N-alkylated derivatives of meridianins have been synthesized as potential antitumor
agents by a two-step conversion of N-tosyl-3-acetylindoles or N-alkyl-3-acetylindoles to the corresponding
enaminones using DMF-DMA, with or without added pyrrolidine. Further cyclization with guanidine gave
the corresponding 2-aminopyrimidines. The structures of the compounds, thus obtained, were proved by 1H
and 13C NMR spectroscopy, NOE experiments and X-ray analysis.
J. Heterocyclic Chem., 44, 793 (2007).
Meridianins show cytotoxicity toward LMM3 (murine
mammarian adenocarcinoma cell line) with IC50 values in
the 10 μM scale and inhibit various protein kinases,
prevent cell proliferation and induce apoptosis as shown
by Gompel M. et al. [10] These results suggest that
meridianins constitute a promising route to more potent
and selective protein kinase inhibitors could be designed.
In order to conduct a detailed structure-activity
relationship (SAR) study we had to develop an
efficient route to analogues and derivatives of these
new marine alkaloids. Three syntheses of natural
meridianines have been described so far: Jiang B. et
al. [11] used the palladium cross-coupling procedure,
between the suitable 3-indolylboronic acid and 2-
amino-4-chloropyrimidine, to get the meridianin D
and its 6-debromoanalogue; Fresneda P. M. et al. [12]
synthesized the meridianins A, C-E from the appro-
priate N-tosyl-3-acetylindoles in two steps: treatment
with dimethylformamide dimethylacetal (DMF-DMA)
[13] and further cyclization of the resulting
enaminones with guanidine [14]. Müller T. J. J.
INTRODUCTION
Marine organisms are very promising sources of
bioactive molecules [1]. Among a huge diversity of
structures indole alkaloids have been isolated from
sponges and tunicates [2] have been considered as lead
compounds for the discovery of new drugs in medicinal
chemistry. Among these, 3-substituted indoles are potent
inhibitors of various protein kinases which show
cytotoxicity towards diverse human tumor cell lines. The
substituent, at the 3-position of the indole ring, is another
heterocyclic ring such as imidazole [3], dihydroimidazole
[3a], maleimide [4], oxazole [5], oxadiazine [6],
piperazine [7], pyrimidine, pyranone and pyrazolol [8]
and 2-aminopyrimidine [9].
Meridianins A-E (Figure 1) which are representatives
of this family of 3-(2-aminopyrimidine)-indoles were
initially isolated [9a] from the sub Antarctic tunicate
Aplidium meridianum.
1'
6'
N
NH2
2'
5'
R1
N
developed
a
carbonylative alkynylation of N1-
4'
3'
4
R2
R3
3
3a
protected-3-iodoindoles using carbon monoxide,
TMS-acetylene and a Pd catalyst [15]. The TMS-
ynones, thus obtained, were proved to be versatile
synthetic equivalents of ꢀ-ketoaldehyde and to
undergo cyclocondensation with guanidine to give the
title compounds in moderate to good yields.
A : R1 = OH R2 = R3 = R4 = H
B : R1 = OH R2 = R4 = H R3 = Br
C : R1 = R3 = R4 = H R2 = Br
D : R1 = R2 = R4 = H R3 = Br
E : R1 = OH R2 = R3 = H R4 = Br
5
2
N
H
1
7a
6
7
R4
Figure 1 - Meridianins A-E.

794
G. Simon, H. Couthon-Gourves, J.-P. Haelters, B. Corbel, N. Kervarec,
F. Michaud and L. Meijer
Vol 44
O
a
b
R
R
R
87-95%
88-97%
N
H
N
N
Ts
Ts
1
3
2
53-84%
c
N
N
NH2
O
O
N
d
+
R
R
R
55-73%
N
N
N
H
CH3
Ts
6
5
4
R = H (a), 4-Cl (b), 5-Cl (c), 6-Cl (d), 4-Br (e), 5-Br (f), 4-F (i), 5-F (j), 6-F (k)
Scheme 1 - Synthesis of meridianin N-H analogues 6a-k. Reagents and conditions: a) TsCl, Bu4N+HSO4 , NaOH 50%, CH2Cl2, RT; b) Ac2O,
-
AlCl3, CH2Cl2, RT; c) DMF-DMA, DMF, 110°C; d) guanidine.HCl, EtONa, EtOH, reflux.
RESULTS AND DISCUSSION
indole ring by DMF-DMA. Alkylating properties of
formamide acetals are well-known [20] and the DMF-
DMA N-methylation of 3-nitroazaindole was reported
[21]. In order to prevent any additional loss of material,
enaminones (fully characterized by 1H and 13C NMR)
were not purified at this stage and used as is in the next
step. Formation of the 2-aminopyrimidine ring and N-
tosyl deprotection were achieved (55-73%), by reacting
crude enaminones 4 with guanidine in ethanol, [22] to
give the N-H meridianin analogues 6 (overall yields 28-
45%).
Our initial attempt to use the Jiang B. et al. [11] cross-
coupling procedure ended in very poor yields of the
expected meridianin analogues. This was probably the
result of the delicate preparation of the corresponding 3-
indolylboronic acid and of capricious palladium cross-
coupling reaction. We then decided to investigate an
alternative route, the linear synthesis previously reported
by Fresneda P. M. et al. [12] Herein, we wish to report the
preparation of N-H and N-alkylated analogues of
meridianins.
Synthesis of N-alkylated meridianin derivatives.
The substitution of a heterocyclic nitrogen atom by an
alkyl group may result in significant modification of the
bioactivity. Indeed, in the purine series, among other
compounds, olomoucine, roscovitine and purvalanol have
been identified as cyclin-dependent kinase inhibitors and
potential anti-tumor agents [23]. Indolic alkaloids such as
keramamide K [24], flustramines A and B [25] or
BG2001 [26] are substituted N-alkylated compounds.
Since we wanted to study the influence of substituents on
the N-indole ring we searched for a practical method to
make the title compounds.
Synthesis of N-H meridianin analogues. Following
the protocol (see Scheme 1), indole precursors 1 [16,17]
were tosylated using a previously reported phase transfer
reaction [18] to give N-tosylindoles 2 in very good yields
(87-95%). We found this protocol more convenient than
sodium hydride anion formation and tosylation (see
Fresneda 2001) [12]. Then, N-tosylindoles 2 were
selectively acylated using aluminium chloride-acetic
anhydride in dichloromethane [19] giving N-tosyl-3-
acetylindoles 3 (88-97% yield). The third step was more
delicate than expected. When compounds 3 were treated
with an excess of dimethylformamide dimethylacetal in
DMF at 110°C, a mixture of two compounds was
obtained: enaminones 4 (53-84%) and N-methyl-3-
N-Alkylated indole derivatives of meridianins were
prepared following the four-step sequence, as described in
Scheme 2.
acetylindoles
5 (16-47%). These N-methyl-3-acetyl-
As mentioned in the first part and according to
monographs [27], the way to get N-alkyl-3-acetylindoles
required, at first, the acetylation and then alkylation. The
best reaction conditions relied upon N-arylsulfonyl
protection before electrophilic acylation [19] as used
above, or the direct acylation of a tin complex [28].
indoles, which were never mentioned in Fresneda's work,
came from the methylation of the N-deprotected acetyl-
indole. The reaction conditions (DMF, 110°C) probably
lead to disproportionation of DMF-DMA, [14a] nucleo-
philic displacement of the tosyl group by methylate or
dimethylamide formed in situ, and N-methylation of the

Jul-Aug 2007
Towards the Syntheses of N-H and N-Alkylated Derivatives of Meridianins
795
O
O
a
b
R
R
R
5
8
51-78%
N
H
58-96%
N
N
H
9
10
11
Alk
1
7
c
90-98%
R = H (a), 4-Cl (b), 5-Cl (c), 6-Cl (d),
4-Br (e), 5-Br (f), 7-Br (g), 4,7-Br (h),
4-F (i), 5-F (j), 6-F (k)
N
N
NH2
O
N
d
5, 12, 17 Alk = CH3
8, 13, 18 Alk = CH2CH3
9, 14, 19 Alk = CH2Ph
10, 15, 20 Alk = CH(CH3)2
11, 16, 21 Alk = CH2CH=C(CH3)2
R
R
17
18
19
20
21
12
13
14
15
16
N
41-84%
N
Alk
Alk
Scheme 2 - Synthesis of meridianin N-alkylated derivatives 17-21. Reagents and conditions: a) Ac2O, SnCl4, CH2Cl2, CH3NO2, RT; b) Alk =
CH3: (CH3)2SO4, Aliquat 336, CH2Cl2, NaOH 50%, RT; Alk = Et: 1) KOH, EtOH 2) BrCH2CH3, acetone, RT; Alk = CH2Ph: BrCH2Ph, KOH,
DMF, RT; Alk = isopropyl: 1) KOH, EtOH 2) isopropyl iodide, acetone, RT; Alk = 3-methyl-2-butenyl: 1) KOH, EtOH 2) BrCH2CH=CH(CH3)2,
acetone, RT; c) DMF-DMA, pyrrolidine, DMF, 110°C; d) guanidine.HCl, EtONa, EtOH, reflux.
We found the Ottoni et al. one-pot protocol [28] more
practical: tin chloride (SnCl4) was first added to a
methylene chloride solution of the indoles, to give a
yellow suspension. Then, acetic anhydride and nitro-
methane (co-solvent) were added to give, after work-up,
3-acetylindoles 7 (51-78%). In step b, depending upon
alkylating reagents, two experimental conditions were
used for the N-alkylation [29]: a phase transfer process
and dimethylsulfate led to N-methylated compounds 5c,
5e, 5g and 5h (72-91%); addition of alkylhalides into
mixtures of potassium hydroxide and indoles in polar
solvents (ethanol, acetone or DMF) to give N-alkylated
compounds 8 to 11 (58-96%). Compounds 5d, 5f and 5k
were by-products of the enaminones syntheses 4 (see part
1). In step c, treating N-alkyl-3-acetylindoles 5 and 7-11
with DMF-DMA in the usual manner led to the
enaminones 12-16 in very poor yields. More vigorous
conditions, a large excess of DMF-DMA and longer
reaction times ended in 40-50% yields of the expected
enaminones. Therefore, changing the N-protecting group
from N-arylsulfonyl, an electrowithdrawing group, to N-
alkyl, lowered the reactivity of the acetyl group towards
DMF-DMA, a reagent that decomposed on extended
heating. According to J. Berger et al. [30] the more stable
Bredereck's reagent [tert-butoxy-bis(dimethylamino)
methane] [31] was used successfully: three equivalents of
the Bredereck's reagent, in DMF, at 110°C, resulted in the
complete conversion of 5a into (2E)-3-(dimethylamino)-
1-(1-methyl-1H-indol-3-yl)-2-propen-1-one, in 4 hours.
However, the price of this reagent is dissuasive enough to
search for other experimental conditions. We found out a
modified Leimgruber-Batcho's procedure [16] more
convenient to make enaminones 12-16: equimolecular
amounts of DMF-DMA and pyrrolidine were heated at
80°C for one hour before adding a DMF solution of 3-
acetylindoles 5 and 7-11. Heating and stirring this mixture
until no starting material was left (2-3 h) and gave, after
workup, enaminones 12-16, in very good yields (90-
98%), which were used as they were in the next step, the
heterocyclization [20]. Upon treatment with guanidine
hydrochloride and sodium ethoxide in refluxing ethanol,
crude enaminones 12-16 led to the N-alkylated meridianin
derivatives 17-21 in 41-84% yields (overall yields 21-
76%).
Structure of 4-(1-methyl-1H-indol-3-yl)-2-pyrimidin-
amine 17a. As mentioned earlier, it has been shown that
meridianins inhibit various protein kinases, prevent cell
proliferation and induce apoptosis [10] but their mode of
action remains unknown.
Recently potent and selective inhibitors of CDKs [32]
and GSK-3 [33] have been studied. These inhibitors act
through competition with ATP binding [34]. The
molecular modelling approach [35] was used to
understand and design new pharmacological inhibitors of
CDKs and GSK-3.
In order to gain insight into the interactions between
meridianin analogues and kinases and to make molecular
mechanics docking-scoring calculation, the structure of
compound 17a was determined by X-ray single crystal
analysis* (see Figure 2). The NMR NOESY spectrum
(see Figure 3) of an acetone-d6 solution of compounds
17a was also recorded.
The ORTEP drawing shows that indole and pyrimidine
rings are twisted with respect to each other with a dihedral

796
G. Simon, H. Couthon-Gourves, J.-P. Haelters, B. Corbel, N. Kervarec,
F. Michaud and L. Meijer
Vol 44
Figure 3 – NOESY spectrum of 4-(1methyl-1H-indole-3-yl)-2-
pyrimidinamine 17a.
Figure 2. ORTEP drawing of the X-ray structure 4-(1-methyl-1H-
indol-3-yl)-2-pyrimidinamine 17a – Crystal structure data: monoclinic
P21/c with a = 10,214(2) Å; b = 8,882(2) Å; c = 12,205(2) Å;
ꢀ = 91,726(15)°; V = 1106.7(4) Å3; Z = 4; n° of observations: 2859.
EXPERIMENTAL
All reagent grade chemicals were used as purchased (Aldrich,
Lancaster). Solvents were purified, when necessary, using
standard procedures. All manipulations were conducted with
magnetic stirring under anhydrous argon or nitrogen.
Chromatography was carried out on silica gel: TLC on silica
gel plates (Merck, art. 5554); column chromatography on silica
gel 60, 70-230 mesh (Merck, art. 10832).
angle of 14.23°. It is worth noting that N1 of the indole
ring, N3' and NH2 of the pyrimidine ring are in a trans
position with respect to each other. The structure
resembles the 2-amino-4-(2-pyridyl) pyrimidine X-ray
structure reported by Balavoine et al. [20a] and to a
lesser extent to 2-amino-3-(H-tosyl-3'-indolyl)-5-
bromopyrazine [36].
Elemental analyses were performed at the CNRS
microanalysis service, ICNS, Gif-sur-Yvette (France).
NMR spectra were obtained on a Brucker DRX 400
spectrometer at 400.13 MHz (1H) and 100.62 MHz (13C) using
CDCl3, DMSO-d6 or acetone-d6 as solvent. Chemical shifts (ꢀ)
are reported in ppm units downfield from TMS (ꢀ = 0.00), traces
of CHCl3, DMSO-d5H, acetone-d5H being used as internal
standard. Coupling constants (J) are in Hz. IR spectra were
recorded on a Perkin Elmer FT IR Spectrometer Spectrum One.
Melting points were measured on a Köffler apparatus and are
uncorrected. Crystal data were collected on an Oxford
Diffraction X-calibur four circle diffractometer (KM4) using Mo
radiation (ꢁ = 0.71073 Å) and a sapphire CCD detector.
The NMR NOESY spectrum analysis of the acetone-d6
solution of compound 17a leads to the same favoured
conformation at room temperature. H2 and H5' are close
together, as shown by the NOE correlation observed
between them (see Figure 3).
These results should help with a molecular modelling
approach of the interaction of meridianin analogues
within the ATP pocket of kinases.
In summary, we have synthesized a series of novel
meridianin N-H and N-alkylated derivatives through
adaptation to previously reported approach [12]. A by-
product which results from N-deprotection of N-tosyl-3-
acetylindole and N-methylation of 3-acetylindole by
DMF-DMA is described. N-alkylated derivatives were
obtained using a modified Batcho et al. procedure,
reacting first DMF-DMA and pyrrolidine before
enaminone formation. Treatment of enaminones with
guanidine leads to 2-aminopyrimidine moiety. These
procedures are quite general and will allow the synthesis
of more complexe analogues to conduct SAR study and
design new kinase inhibitors for anticancer drug research.
Studies of the structure-activity relationship are currently
underway and will be reported elsewhere.
General procedure for N-tosylated indoles (2). To a
solution of indole (8.5 mmol) and tetrabutylammonium
hydrogen sulfate (162 mg, 0.85 mmol) of in CH2Cl2 (25 mL)
was added NaOH 50% (5 mL). After stirring a few minutes, p-
toluenesulfonylchloride (1.8 g, 12.75 mmol) was added to the
reaction mixture, which was then stirred vigorously at room
temperature for 3 h. The solution was poured into water and
extracted with dichloromethane. The combined organic layers
were dried (MgSO4) and concentrated to dryness. The remaining
solid was recrystallized from toluene to give 2.
General procedure for N-tosylated 3-acetylindoles (3). To a
suspension of aluminium chloride (13.6 g, 72.0 mmol) in
dichloromethane (160 mL) was added acetic anhydride (4.7 mL,
51.0 mmol). The reaction mixture was stirred until AlCl3 was
completely dissolved. Then, 2 (17.0 mmol) in dichloromethane
(15 mL) was added to the solution and a vigorous stirring was
kept at room temperature for 3 h. The resulting mixture was

Jul-Aug 2007
Towards the Syntheses of N-H and N-Alkylated Derivatives of Meridianins
797
washed with brine, saturated NaHCO3 solution and brine. The
organic layer was dried (MgSO4), filtered and concentrated to
dryness. The brown solid thus obtained was recrystallized from
ether to give a white powder.
General procedure for enaminones (4). To a solution of 3
(4.0 mmol) in dry DMF (5 mL) was added a solution of
dimethylformamide dimethylacetal (0.75 mL, 6.0 mmol) in the
same solvent (2 mL). The resultant solution was heated at 110°C
for 4 h. After cooling, the solution was poured into water and
then extracted with EtOAc. The combined organic layers were
dried (MgSO4) and concentrated to dryness under reduce
pressure. The residue can be recrystallized from ether to give
yellow prisms.
General procedure for 3-acetylindoles (7). To a stirring
solution of indole (10.0 mmol) in CH2Cl2 (20 mL) at 0°C, SnCl4
(1.44 mL, 12.0 mmol) was added in a single portion. After the
ice bath was removed, the mixture was stirred at room
temperature for 30 min, and then acetic anhydride (2.1 mL, 10.0
mmol) was added in small portions to the suspension, followed
by nitromethane (15 mL). The mixture was stirred for 3 h at
room temperature. After being quenched with ice and water (30
mL), the mixture was filtered to remove inorganic precipitates,
and the organic material was extracted with ethyl acetate. The
organic phase was dried over MgSO4 and concentrated at reduce
pressure to give the product as a solid which was recrystallized
from chloroform to give colourless prisms.
General procedure for N-methylated 3-acetylindoles (5). A
mixture of 7 (13.2 mmol), Aliquat 336 (85 mg, 0.2 mmol),
dimethyl sulfate (1.50 mL, 15.8 mmol), CH2Cl2 (20 mL) and
50% NaOH aqueous solution (10 mL) was stirred vigorously for
1 hour until TLC did not detect 7. The organic solution was
separated, washed with water, dried with MgSO4 and
concentrated to give a solid that was recrystallized from toluene
to give colourless prisms.
General procedure for N-ethylated 3-acetylindoles (8). To
a solution of 7 (11.7 mmol) in ethanol (30 mL) at room
temperature, KOH pellets were added (0.83 g, 17.6 mmol), and
the mixture was stirred until total solubilization. The ethanol
was completely removed in vacuo and replaced by acetone (30
mL). Ethyl bromide (0.87 mL, 11.7 mmol) was added and a
precipitate formed instantly. The solid was filtered and the
solution concentrated in vacuo. The residue was chroma-
tographed on silica gel column using EtOAc/hexane 1/1 as
eluent to give colourless prisms.
General procedure for N-benzylated 3-acetylindoles (9). A
mixture of KOH pellets (0.30 g, 5.4 mmol) and 7 (3.6 mmol) in
dry DMF (10 mL) was stirred at room temperature until
solubilization of the KOH pellets. Benzyl bromide (0.50 mL, 3.9
mmol) was then added and the reaction mixture was stirred until
TLC did not detect 3-acetylindole. The mixture was poured into
water and the product extracted with EtOAc. The organic layer
was dried (MgSO4) and concentrated under reduce pressure. The
residue is recrystallized from ether to give colourless prisms.
General procedure for N-isopropylated 3-acetylindoles
(10). KOH pellets were added (0.23 g, 3.9 mmol) to a solution
of 7 (3.1 mmol) in ethanol (10 mL) and the mixture was stirred,
at room temperature, until total solubilization. The ethanol was
completely removed in vacuo and replaced by acetone (10 mL).
Isopropyl iodide (0.58 g, 3.4 mmol) was added and a precipitate
formed instantly. The solid was filtered and the solution
concentrated in vacuo. Column chromatography of the residue
on silica gel (EtOAc/hexane: 1/3) gave 10 as colourless prisms.
General procedure for N-(3-methyl-2-butenyl) 3-acetyl-
indoles (11). KOH pellets were added (0.36 g, 6.3 mmol) to a
solution of 7 (5.0 mmol) in ethanol (20 mL) and the mixture was
stirred, at room temperature, until total solubilization. The
ethanol was completely removed in vacuo and replaced by
acetone (20 mL). 3-Methyl-2-butenyl bromide (0.75 g, 5.0
mmol) was added and a precipitate formed instantly. The solid
was filtered and the solution concentrated in vacuo. Column
chromatography of the residue on a silica gel (EtOAc/hexane:
1/3) gave colourless oil.
General procedure for enaminones (12-16). DMF-DMA
(0.31 mL, 2.6 mmol) and pyrrolidine (0.21 mL, 2.6 mmol) were
heated under stirring for 1 h at 80°C. Then, 5 (1.7 mmol) in
DMF (2 mL) was added and the reaction mixture was heated at
110°C and the stirring was continued until TLC did not detect
any starting material. After cooling, the solution was poured into
EtOAc and washed with water. The organic layer was dried
(MgSO4) and concentrated at reduce pressure to give a red oil.
This crude product was used with no more purification in the
next step.
General procedure for analogues (6) and derivatives (17-
21). To a solution of 4 (2.9 mmol) and guanidine hydrochloride
(0.35 g, 3.6 mmol) in refluxing ethanol (5 mL) was added a
solution of sodium (0.13 g, 5.8 mmol) in ethanol (10 mL). The
resulting mixture was heated at reflux for 24 h. After cooling,
the solution was poured into water and then extracted with
EtOAc. The combined organic layers were dried (MgSO4) and
concentrated to dryness under reduced pressure. The remaining
residue was recrystallized from chloroform to give the title
compounds.
4-(1H-Indol-3-yl)-2-pyrimidinamine (6a). Yellow powder
(62%); mp 183-185°C; 1H NMR (acetone-d6): ꢀ 5.91 (brs, NH2),
7.04 (d, 1H, J=5.3, H5'), 7.10-7.22 (m, 2H, H5, H6), 7.46 (d, 1H,
J=7.3, H7), 8.12 (m, 2H, H6', H2), 8.58 (d, 1H, J=7.7, H4),
10.86 (brs, NH); 13C NMR (acetone-d6): ꢀ 111.5 (C5'), 117.2
(C7), 120.2 (C3), 126.0/127.7/128.0 (C4/C5/C6), 131.4 (C3a),
133.0 (C2), 143.0 (C7a), 162.7 (C6'), 168.7/169.5 (C2'/C4'); IR
(KBr): 3408, 3329, 3173, 1660, 1568, 1520, 1452, 1413, 1246,
751, 735 cm-1. Anal. Calcd. for C12H10N4 (210.24): C 68.56, H
4.79. Found: C 68.45, H 4.78.
4-(4-Chloro-1H-indol-3-yl)-2-pyrimidinamine (6b). Yellow
prisms (55%); mp 202-204°C; 1H NMR (acetone-d6): ꢀ 5.79 (brs
NH2), 6.92 (d, 1H, J=4.9, H5'), 7.12-7.18 (m, 2H, H5, H6), 7.49
(dd, 1H, J=7.1, 2.0, H7), 7.76 (s, 1H, H2), 8.19 (d, 1H, J=4.9,
H6'), 10.88 (brs, NH); 13C NMR (acetone-d6): ꢀ 111.8 (C5'),
112.9 (C7), 117.5 (C3), 122.4/123.5 (C5/C6), 126.3/129.4
(C4/C3a), 129.5 (C2), 139.5 (C7a), 157.4 (C6'), 163.2/164.4
(C2'/C4'); IR (KBr): 3395, 3319, 3173, 2926, 1647, 1576, 1524,
1489, 1464, 1310, 1254, 1170, 825, 777, 739 cm-1. Anal. Calcd.
for C12H9ClN4 (244.68): C 58.90, H 3.71. Found: C 58.76, H
3.62.
4-(5-Chloro-1H-indol-3-yl)-2-pyrimidinamine (6c). Yellow
prisms (67%); mp 239-241°C; 1H NMR (acetone-d6): ꢀ 5.96
(brs, NH2), 7.02 (d, 1H, J=5.3, H5'), 7.17 (dd, 1H, J=8.6, 2.1,
H6), 7.48 (d, 1H, J=8.6, H7), 8.13 (d, 1H, J=5.3, H6'), 8.19 (s,
1H, H2), 8.67 (d, 1H, J=2.1, H4), 10.91 (brs, NH); 13C
NMR (DMSO-d6): ꢀ 105.2 (C3), 113.4/113.6 (C5'/C7), 121.7/
122.1 (C4/C6), 125.2 (C2), 126.6/130.0 (C3a/C5), 135.7 (C7a),
157.3 (C6'), 162.5/163.8 (C4'/C2'); IR (KBr): 3506, 3477, 3373,
3119, 2872, 1574, 1548, 1528, 1455, 1423, 1220, 802, 672 cm-1.
Anal. Calcd. for C12H9ClN4 (244.68): C 58.90, H 3.71. Found: C
58.80, H 3.58.

798
G. Simon, H. Couthon-Gourves, J.-P. Haelters, B. Corbel, N. Kervarec,
F. Michaud and L. Meijer
Vol 44
4-(6-Chloro-1H-indol-3-yl)-2-pyrimidinamine (6d). Yellow
1
IR (KBr): 3497, 3324, 3172, 2919, 1634, 1576, 1540, 1454,
1143, 808 cm-1. Anal. Calcd. for C12H9FN4 (228.23): C 63.15, H
3.97. Found: C 63.04, H 3.92.
4-(1-Methyl-1H-indol-3-yl)-2-pyrimidinamine (17a). Yellow
1
prisms (81%); mp 216-218°C; H NMR (DMSO-d6): ꢀ 3.86 (s,
3H, CH3), 5.07 (brs, NH2), 6.99 (d, 1H, J=5.4, H5'), 7.25-7.39
(m, 3H, H5, H6, H7), 7.79 (s, 1H, H2), 8.22 (d, 1H, J=5.4, H6'),
8.35 (m, 1H, H4); 13C NMR (DMSO-d6): ꢀ 33.4 (CH3), 107.2
(C5'), 109.9 (C7), 113.5 (C3), 121.5/121.7/ 122.8 (C4/C5/C6),
125.9 (C3a), 131.7 (C2), 137.9 (C7a), 156.3 (C6'), 162.3 (C4'),
163.1 (C2'); IR (KBr): 3454, 3288, 3153, 2934, 1625, 1575,
1534, 1480, 1456, 1418, 1371, 1235, 1218, 1105, 743 cm-1.
Anal. Calcd. for C13H12N4 (224.26): C 69.62, H 5.39. Found: C
69.54, H 5.31.
prisms (73%); mp 192-194°C; H NMR (acetone-d6): ꢀ 5.93
(brs NH2), 7.03 (d, 1H, J=5.3, H5'), 7.12 (dd, 1H, J=8.5, 1.7,
H5), 7.51 (d, 1H, J=1.7, H7), 8.14 (d, 1H, J=5.3, H6'), 8.17 (s,
1H, H2), 8.61 (d, 1H, J=8.5, H4), 10.91 (brs NH); 13C
NMR (acetone-d6): ꢀ 106.7 (C5'), 112.3 (C7), 115.6 (C3), 121.6/
124.7 (C4/C5), 125.4/128.4/129.1 (C2/C6/C3a), 138.6 (C7a),
158.2 (C6'), 163.6/164.7 (C4'/C2'); IR (KBr): 3445, 3168, 1661,
1573, 1518, 1448, 816 cm-1. Anal. Calcd. for C12H9ClN4
(244.68): C 58.90, H 3.71. Found: C 58.78, H 3.64.
4-(4-Bromo-1H-indol-3-yl)-2-pyrimidinamine (6e). Yellow
prisms (67%); mp 217-219°C; 1H NMR (acetone-d6): ꢀ 5.77 (brs
NH2), 6.86 (d, 1H, J=5.1, H5'), 7.08 (t, 1H, J=7.9, H6), 7.32 (d,
1H, J=7.6, H7), 7.53 (d, 1H, J=8.2, H5),7.70 (s, 1H, H2), 8.19
(d, 1H, J=5.1, H6'), 10.91 (brs NH). 13C NMR (acetone-d6): ꢀ
112.3 (C7), 113.5 (C5'), 114.3 (C3), 123.7/125.1 (C5/C6),
129.1/129.2 (C4/ C3a), 138.9 (C7a), 157.3 (C6'), 163.2/164.4
(C4'/C2'); IR (KBr): 3408, 3304, 3158, 1648, 1578, 1527, 1464,
1310, 738 cm-1. Anal. Calcd. for C12H9BrN4 (289.13): C 49.85, H
3.14. Found: C 49.70, H 3.12.
4-(5-Bromo-1H-indol-3-yl)-2-pyrimidinamine (6f). Yellow
prisms (57%); mp 106-108°C, litt.[9a] 103-106°C; 1H NMR
(acetone-d6): ꢀ 5.61 (brs NH2), 7.02 (d, 1H, J=5.3, H5'), 7.29
(dd, 1H, J=8.6, 2.0, H6), 7.43 (d, 1H, J=8.6, H7), 8.14 (d, 1H,
J=5.3, H6'), 8.18 (m, 1H, H2), 8.83 (d, 1H, J=2.0, H4), 10.83
(brs NH); 13C NMR (acetone-d6): ꢀ 106.4 (C5'), 114.1 (C7),
114.3 (C3), 115.0 (C5), 127.7 (C4, C6), 128.2 (C3a), 129.4 (C2),
136.8 (C7a), 158.1 (C6'), 163.4/164.7 (C4'/C2'); IR (KBr): 3476,
3371, 3120, 1576, 1527, 1453, 1419, 1332, 1291, 1212, 800, 658
cm-1. Anal. Calcd. for C12H9BrN4 (289.13): C 49.85, H 3.14.
Found: C 49.72, H 3.10.
4-(4-Fluoro-1H-indol-3-yl)-2-pyrimidinamine (6i). Colourless
prisms (61%); mp 188-190°C; 1H NMR (acetone-d6): ꢀ 5.73 (brs
NH2), 6.88 (dd, 1H, J=7.8, 12.4, H5), 7.15 (m, 2H, H6, H5'),
7.35 (d, 1H, J=8.1, H7), 8.10 (s, 1H, H2), 8.22 (d, 1H, J=5.3,
H6'), 11.02 (brs, NH); 13C NMR (acetone-d6): ꢀ 105.8 (C5, d,
J=22), 107.6 (C3, d, J=14), 108.9 (C5), 112.8 (C3a, d, J=19),
113.8 (C7), 122.6 (C6, d, J=8), 128.8 (C2), 140.0 (C7a, d, J=11),
155.5 (C4, d, J=245), 157.9 (C6'), 160.8/163.4 (C2'/C4'); IR
(KBr): 3397, 3320, 3182, 1655, 1567, 1506, 1475, 1457, 1417,
1356, 1417, 1356, 1318, 1229, 1122, 1036, 1028, 821, 781, 774,
743, 730, 707 cm-1. Anal. Calcd. for C12H9FN4 (228.23): C 63.15,
H 3.97. Found: C 63.02, H 3.86.
4-(5-Fluoro-1H-indol-3-yl)-2-pyrimidinamine (6j). Colourless
prisms (69%); mp 160-162°C; 1H NMR (acetone-d6): ꢀ 5.91 (brs
NH2), 6.98 (td, 1H, J=9.2, 2.6, H6), 7.01 (d, 1H, J=5.4, H5'),
7.46 (dd, 1H, J=8.8, 4.6, H7), 8.14 (d, 1H, J=5.4, H6'), 8.20 (d,
1H, J=1.8, H2), 8.36 (dd, 1H, J=2.6, 9.4, H4), 10.87 (brs, NH);
13C NMR (acetone-d6): ꢀ 106.4 (C5'), 108.4 (C4, d, J=9), 111.2
(C6, d, J=27), 113.4 (C7, d, J=10), 130.3 (C2), 157.7 (C2'),
157.9 (C6'), 161.5 (C5, d, J=235), 164.7 (C4'); IR (KBr): 3415,
3329, 3180, 1658, 1569, 1520, 1486, 1453, 1235, 1181, 806, 793
cm-1. Anal. Calcd. for C12H9FN4 (228.23): C 63.15, H 3.97.
Found: C 62.99, H 3.88.
4-(6-Fluoro-1H-indol-3-yl)-2-pyrimidinamine (6k). Yellow
prisms (63%); mp 230-232°C; 1H NMR (acetone-d6): ꢀ 5.61 (brs
NH2), 6.93 (td, 1H, J=2.1, 8.9, H5), 7.02 (d, 1H, J=5.3, H5'),
7.20 (dd, 1H, J=9.8, 2.1, H7), 8.13 (m, 2H, H6', H2), 8.63 (dd,
1H, J=8.9, 5.7, H4), 10.83 (brs, NH); 13C NMR (acetone-d6): ꢀ
98.5 (C7, d, J=26), 106.6 (C5'), 109.6 (C5, d, J=24), 115.6 (C3),
123.4 (C3a), 124.7 (C4, d, J=10), 128.2 (C2), 138.2 (C7a, d,
J=8), 158.1 (C6'), 160.8 (C6, d, J=235), 163.7/164.8 (C2'/C4');
4-(5-Chloro-1-methyl-1H-indol-3-yl)-2-pyrimidinamine (17c).
1
Yellow prisms (55%); mp 224-226°C; H NMR (acetone-d6): ꢀ
3.92 (s, 3H, CH3), 5.96 (brs, NH2), 6.96 (d, 1H, J=5.2, H5'), 7.22
(d, 1H, J=8.2, H6), 7.42 (d, 1H, J=8.2, H7), 8.13 (m, 2H, H2,
H6'), 8.67 (s, 1H, H4); 13C NMR (DMSO-d6): ꢀ 35.3 (CH3),
105.2 (C3), 111.9/112.3 (C7/C5'), 121.7/122.1 (C4/C6),
125.6/126.7 (C3a/C5), 133.7/136.1 (C7a/C2), 157.0 (C6'), 162.0/
163.4 (C4'/C2'); IR (KBr): 3467, 3289, 3146, 1627, 1571, 1533,
1462, 1420, 1368, 1217, 1106, 799, 681 cm-1. Anal. Calcd. for
C13H11ClN4 (258.71): C 60.35, H 4.29. Found: C 60.25, H 4.18.
4-(6-Chloro-1-methyl-1H-indol-3-yl)-2-pyrimidinamine (17d).
1
Yellow prisms (46%); mp 239-241°C; H NMR (acetone-d6): ꢀ
3.89 (s, 3H, CH3), 5.74 (brs, NH2), 6.89 (d, 1H, J=5.1, H5'), 7.23
(m, 2H, H4, H7), 7.46 (dd, 1H, J=8.1, 1.0, H5), 7.68 (s, 1H, H2),
8.18 (d, 1H, J=5.1, H6'); 13C NMR (acetone-d6): ꢀ 33.1 (CH3),
104.2 (C3), 110.0 (C5'), 112.9 (C7), 122.5 (C4/C5), 123.0
(C6/C3a), 123.3 (C4/C5), 126.3 (C6/C3a), 133.7 (C2), 140.5
(C7a), 157.4 (C6'), 163.0/164.4 (C4'/C2'); IR (KBr): 3312, 3160,
1658, 1568, 1523, 1463, 1418, 1315, 1198, 1119, 812 cm-1.
Anal. Calcd. for C13H11ClN4 (258.71): C 60.35, H 4.29. Found: C
60.26, H 4.20.
4-(4-Bromo-1-methyl-1H-indol-3-yl)-2-pyrimidinamine (17e).
1
Yellow prisms (65%); mp 250-252°C; H NMR (DMSO-d6): ꢀ
3.84 (s, 3H, CH3), 6.43 (brs, NH2), 6.73 (d, 1H, J=5.3, H5'),
7.13 (t, 1H, J=7.8, H6), 7.33 (d, 1H, J=7.5, H5/H7), 7.57 (d,
1H, J=8.0, H5/H7), 7.95 (s, 1H, H2), 8.16 (d, 1H, J=5.1, H6');
13C NMR (DMSO-d6): ꢀ 33.0 (CH3), 110.1/111.8/113.1/114.8
(C5/C7/C5'/C3), 122.9/123.9/125.0 (C4/C6/C3a), 133.2 (C7a),
138.2 (C2), 155.5 (C6'), 161.9/162.2 (C4'/C2'); IR (KBr): 3320,
3165, 1656, 1563, 1536, 1518, 1459, 1414, 1245, 1194, 1112,
774, 739 cm-1. Anal. Calcd. for C13H11BrN4 (303.16): C 51.50,
H 3.66. Found: C 51.37, H 3.56.
4-(5-Bromo-1-methyl-1H-indol-3-yl)-2-pyrimidinamine (17f).
1
Yellow powder (65%); mp 214-216°C; H NMR (acetone-d6): ꢀ
3.84 (s, 3H, CH3), 5.13 (brs, NH2), 6.89 (d, 1H, J=5.3, H5'), 7.21
(d, 1H, J=8.8, H7), 7.39 (d, 1H, J=8.8, H6), 7.73 (s, 1H, H2),
8.21 (d, 1H, J=5.3, H6'), 8.57 (s, 1H, H4); 13C NMR (CDCl3): ꢀ
33.5 (CH3), 107.1 (C4), 111.2 (C5'), 113.3 (C3), 114.9 (C6),
124.6/125.6 (C2/C7), 127.5 (C7a), 131.9 (C5), 136.5 (C3a),
157.4 (C6'), 162.4/162.9 (C2'/C4'); IR (KBr): 3457, 3285, 3144,
1629, 1572, 1534, 1462, 1420, 1372, 1219, 799, 680 cm-1. Anal.
Calcd. for C13H11BrN4 (303.16): C 51.50, H 3.66. Found: C
51.43, H 3.55.
4-(7-Bromo-1-methyl-1H-indol-3-yl)-2-pyrimidinamine (17g).
1
Yellow powder (78%); mp 175-177°C; H NMR (acetone-d6): ꢀ
4.17 (s, 3H, CH3), 6.48 (brs, NH2), 6.92 (d, 1H, J=5.4, H5'), 7.03 (t,
1H, J=7.7, H5), 7.38 (d, 1H, J=8.0, H6), 8.12 (d, 1H, J=5.4, H6'),
8.24 (s, 1H, H2), 8.70 (d, 1H, J=7.6, H4); 13C NMR (acetone-d6): ꢀ

Jul-Aug 2007
Towards the Syntheses of N-H and N-Alkylated Derivatives of Meridianins
799
38.8 (CH3), 105.4/108.8/110.7 (C7/C3/ C5'), 116.8/122.4 (C4/C5),
132.8 (C3a), 137.9/139.8 (C2/C7a), 157.8 (C6'), 161.0/162.9
(C4'/C2'); IR (KBr): 3316, 3162, 1653, 1562, 1524, 1461, 1408,
1303, 1075, 811, 738 cm-1. Anal. Calcd. for C13H11BrN4 (303.16):
C 51.50, H 3.66. Found: C 51.36, H 3.62.
1220, 1204, 1110, 824, 816, 804, 786, 681,581 cm-1. Anal.
Calcd. for C14H13BrN4 (317.18): C 53.01, H 4.13. Found: C
52.89, H 4.09.
4-(4,7-Dibromo-1-ethyl-1H-indol-3-yl)-2-pyrimidinamine
(18h). Yellow prisms (76%); mp 173-175°C; 1H NMR (DMSO-
d6): ꢀ 1.39 (t, 3H, J=7.0, CH3), 4.63 (q, 2H, J=7.0, CH2), 6.51
(brs, NH2), 6.67 (d, 1H, J=5.3, H5'), 7.21 (d, 1H, J=8.2, H5/H6),
7.33 (d, 1H, J=8.2, H5/H6), 7.80 (s, 1H, H2), 8.18 (d, 1H, J=5.3,
H6');13C NMR (DMSO-d6): ꢀ 15.3 (CH3), 40.8 (CH2), 102.7
(C5'), 105.6/106.7/108.2 (C3, C4, C7), 113.0/116.0 (C5, C6),
127.0/127.9 (C2, C3a), 132.3 (C7a), 156.7 (C6'), 161.2/163.0
(C2', C4'); IR (KBr): 3306, 3169, 2980, 1650, 1570, 1524, 1471,
1390, 1323, 1231, 1216, 1186, 1115, 1076, 1016, 869, 817, 791,
668 cm-1. Anal. Calcd. for C14H12Br2N4 (396.08): C 42.45, H
3.05. Found: C 42.34, H 3.01.
4-(4,7-Dibromo-1-methyl-1H-indol-3-yl)-2-pyrimidinamine
(17h). Yellow powder (71%); mp 218-220°C; 1H NMR
(acetone-d6): ꢀ 4.17 (s, 3H, CH3), 6.50 (brs, NH2), 6.66 (d, 1H,
J=5.4, H5'), 7.21 (d, 1H, J=8.0, H5/H6), 7.32 (d, 1H, J=8.0,
H5/H6), 7.73 (s, 1H, H2), 8.18 (d, 1H, J=5.4, H6'); 13C
NMR (acetone-d6): ꢀ 37.1 (CH3), 103.2 (C3), 112.9/115.4
(C4/C7), 125.8/ 126.7/127.5 (C5/C6/C3a), 133.5/135.4 (C7a/
C2), 156.6 (C6'), 161.2/163.0 (C4'/C2'); IR (KBr): 3411, 3308,
3154, 1639, 1576, 1556, 1458, 1430, 1389, 1309, 1193, 1112,
1099, 1067, 1010, 867, 818, 797, 680 cm-1. Anal. Calcd. for
C13H10Br2N4 (382.05): C 40.87, H 2.64. Found: C 40.70, H 2.58.
4-(6-Fluoro-1-methyl-1H-indol-3-yl)-2-pyrimidinamine (17k).
4-(1-Ethyl-5-fluoro-1H-indol-3-yl)-2-pyrimidinamine (18j).
1
Yellow prisms (51%); mp 165-167°C; H NMR (DMSO-d6): ꢀ
1
Yellow prisms (44%); mp 210-213°C; H NMR (acetone-d6): ꢀ
1.40 (t, 3H, J=7.3, CH3), 4.24 (d, 2H, J=7.3, CH2), 6.42 (brs,
NH2), 6.94 (d, 1H, J=5.3, H5'), 7.05 (td, 1H, J=9.1, 2.5, H6),
7.55 (dd, 1H, J=8.9, 4.6, H7), 8.09 (d, 1H, J=5.3, H6'), 8.32 (s,
1H, H2), 8.38 (dd, 1H, J=10.6, 2.5, H4); 13C NMR (DMSO-d6):
ꢀ 15.2 (CH3), 41.0 (CH2), 104.8 (C5'), 107.6 (C4/C6, d, J=25),
110.0 (C4/C6, d, J=26), 111.3 (C3a, d, J=10), 112.7 (C3), 126.2
(C7, d, J=11), 132.1 (C7a), 133.2 (C2), 157.0 (C6'), 158.2 (C5',
d, J=233), 162.0/163.4 (C2'/C4'); IR (KBr): 3470, 3285, 3143,
2972, 2935, 1628, 1573, 1534, 1481, 1456, 1397, 1337, 1213,
1198, 1110, 804, 695 cm-1. Anal. Calcd. for C14H13FN4 (256.28):
C 65.61, H 5.11. Found: C 65.56, H 5.09.
3.86 (s, 3H, CH3), 5.82 (brs, NH2), 6.95 (m, 2H, J=2.3, 8.9, H5,
H5'), 7.22 (dd, 1H, J=2.3, 9.9, H7), 8.05 (s, 1H, H2), 8.13
(d, 1H, J=5.4, H6'), 8.62 (dd, 1H, J=8.9, 5.7, H4); 13C
NMR (acetone-d6): ꢀ 33.5 (CH3), 96.9 (C7, d, J=25), 106.8
(C5'), 109.5 (C5, d, J=25), 115.0 (C3), 124.3 (C3a), 124.9 (C4,
d, J=9), 132.9 (C2), 139.2 (C7a, d, J=10), 158.1 (C6'), 160.8
(C6, d, J=235), 163.5/164.9 (C2'/C4'); IR (KBr): 3454, 3266,
3133, 1628, 1580, 1533, 1454, 1418, 1364, 1332, 1242, 1221,
1173, 1093, 928, 836, 819, 798, 678 cm-1. Anal. Calcd. for
C13H11FN4 (242.25): C 64.45, H 4.58. Found: C 64.32, H 4.47.
4-(1-Ethyl-1H-indol-3-yl)-2-pyrimidinamine (18a). Yellow
4-(1-Benzyl-1H-indol-3-yl)-2-pyrimidinamine (19a). Colourless
1
1
prisms (65%); mp 142-144°C; H NMR (DMSO-d6): ꢀ 1.40 (t,
prisms (56%); mp 162-164°C; H NMR (acetone-d6): ꢀ 5.52 (s,
3H, J=7.3, CH3), 4.24 (d, 2H, J=7.3, CH2), 6.42 (brs, NH2), 6.95
(d, 1H, J=5.3, H5'), 7.14 (t, 1H, H5/H6), 7.21 (t, 1H, H5/H6),
7.52 (d, 1H, J=8.0, H7), 8.10 (d, 1H, J=5.3, H6'), 8.23 (s, 1H,
H2), 8.58 (d, 1H, J=8.0, H4); 13C NMR (DMSO-d6): ꢀ 15.3
(CH3), 40.8 (CH2), 105.2 (C3), 110.2 (C5'), 112.9 (C7),
120.5/122.0 (C4/C5/C6), 122.7 (C3a), 125.9 (C4/C5/C6), 130.6
(C7a), 136.5 (C2), 157.0 (C6'), 162.3/163.5 (C4'/C2'); IR (KBr):
3304, 3168, 2976, 1663, 1571, 1562, 1521, 1462, 1394, 1216,
811, 749 cm-1. Anal. Calcd. for C14H14N4 (238.29): C 70.57, H
5.92. Found: C 70.58, H 5.90.
2H, CH2), 5.85 (brs, NH2), 7.02 (d, 1H, J=5.3, H5'), 7.16 (m, 2H,
H5, H6), 7.24-7.34 (m, 5H, Ph), 7.45 (d, 1H, J=7.2, H7), 8.13 (d,
1H, J=5.3, H6'), 8.22 (s, 1H, H2), 8.59 (dd, 1H, J=1.8, 7.0, H4);
13C NMR (DMSO-d6): ꢀ 50.0 (CH2), 105.4 (C3), 111.0 (C5'),
113.6 (C7), 120.9/122.3/122.8 (C4/C5/C6), 126.2 (C3a), 127.4
(2C, Ph), 127.9 (C, Ph), 129.0 (2C, Ph), 131.8 (C2), 136.9/137.8
(C, Ph/C7a), 157.1 (C6'), 161.9/163.7 (C4'/C2'); IR (KBr): 3454,
1624, 1573, 1532, 1455, 1388, 1182, 743 cm-1. Anal. Calcd. for
C19H16N4 (300.36): C 75.98, H 5.37. Found: C 75.87, H 5.35.
4-(1-Benzyl-6-chloro-1H-indol-3-yl)-2-pyrimidinamine (19d).
1
4-(5-Chloro-1-ethyl-1H-indol-3-yl)-2-pyrimidinamine (18c).
1
Yellow prisms (84%); mp 155-157°C; H NMR (DMSO-d6): ꢀ
Yellow prisms (63%); mp 166-168°C; H NMR (acetone-d6): ꢀ
5.49 (s, 2H, CH2), 6.49 (brs, NH2), 6.96 (d, 1H, J=5.3, H5'), 7.13
(dd, 1H, J=1.9, 8.6 Hz, H5), 7.22-7.35 (m, 5H, Ph), 7.67 (d, 1H,
J=1.9, H7), 8.12 (d, 1H, J=5.3, H6'), 8.42 (s, 1H, H2), 8.60 (d,
1H, J=8.6, H4); 13C NMR (acetone-d6): ꢀ 49.5 (CH2), 105.3
(C3), 110.6 (C5'), 113.6 (C7), 120.9 (C4/C5), 124.1 (C6), 124.7
(C4/C5), 127.2 (2C, Ph), 127.3 (C3a), 127.7 (C, Ph), 128.7 (2C,
Ph), 132.4 (C7a), 137.2/137.3 (C2/C, Ph), 157.4 (C6'),
161.7/163.5 (C2'/C4'); IR (KBr): 3454, 3283, 3141, 2926, 1625,
1551, 1573, 1529, 1455, 1376, 1176, 816, 699 cm-1. Anal.
Calcd. for C19H15ClN4 (334.80): C 68.16, H 4.52. Found: C
68.22, H 4.51.
1.40 (t, 3H, J=7.3, CH3), 4.24 (q, 2H, J=7.3, CH2), 6.50 (brs,
NH2), 6.94 (d, 1H, J=5.3, H5'), 7.21 (dd, 1H, J=8.7, 2.1, H6),
7.57 (d, 1H, J=7.9, H7), 8.10 (d, 1H, J=5.3, H6'), 8.33 (s, 1H,
H2), 8.63 (d, 1H, J=2.1, H4); 13C NMR (DMSO-d6): ꢀ 15.3
(CH3), 40.9 (CH2), 109.7/111.5/114.7 (C3/C7/C5'), 121.5/
122.4/122.6/124.8 (C5/C6/C4/C3a), 131.5/137.5 (C2/C7a),
156.4 (C6'), 161.6/ 163.1 (C4'/C2'); IR (KBr): 3452, 3296, 3155,
2973, 1626, 1575, 1533, 1458, 1430, 1396, 1335, 1210, 1145,
792, 680 cm-1. Anal. Calcd. for C14H13ClN4 (272.73): C 61.65, H
4.80. Found: C 61.63, H 4.79.
4-(7-Bromo-1-ethyl-1H-indol-3-yl)-2-pyrimidinamine (18g).
Yellow prisms (67%); mp 165-167°C; 1H NMR (DMSO-d6):
ꢀ 1.42 (t, 3H, J=7.1, CH3), 4.62 (q, 2H, J=7.1, CH2), 6.49 (brs,
NH2), 6.95 (d, 1H, J=5.4, H5'), 7.05 (t, 1H, J=7.8, H5), 7.42 (d,
1H, J=7.7, H6), 8.13 (d, 1H, J=5.4, H6'), 8.31 (s, 1H, H2), 8.73
(d, 1H, J=7.9, H4); 13C NMR (DMSO-d6): ꢀ 15.4 (CH3), 40.9
(CH2), 102.9 (C5'), 105.5 (C3), 113.0 (C7), 122.4/122.8/127.3
(C4, C5, C6), 129.4/132.5 (C2, C3a), 134.1 (C7a), 157.4 (C6'),
161.5/163.5 (C2', C4'); IR (KBr): 3328, 3193, 3126, 2974, 2922,
1651, 1573, 1554, 1534, 1481, 1469, 1450, 1413, 1385, 1327,
4-(1-Benzyl-5-bromo-1H-indol-3-yl)-2-pyrimidinamine (19f).
Yellow prisms (71%); mp 208-210°C; H NMR (acetone-d6): ꢀ
1
5.55 (s, 2H, CH2), 6.02 (brs, NH2), 7.00 (d, 1H, J=5.3, H5'),
7.27-7.34 (m, 6H, H6, Ph), 7.42 (d, 1H, J=8.7, H7), 8.14 (d, 1H,
J=5.3, H6'), 8.38 (s, 1H, H2), 8.85 (d, 1H, J=2.0, H4); 13C
NMR (DMSO-d6): ꢀ 53.1 (CH2), 108.7 (C3), 116.3/116.4/117.3
(C4/C7/C5'), 128.2/128.3 (C5/C6), 130.6 (2C, Ph), 131.0/131.1
(C, Ph/C3a), 132.2 (2C, Ph), 136.3/139.0/140.7 (C2/C7a/C, Ph),
160.8 (C6'), 165.2/167.0 (C4'/C2'); IR (KBr): 3480, 3290, 3151,
3000, 2929, 1627, 1578, 1536, 1463, 1433, 1392, 1190, 1181,

800
G. Simon, H. Couthon-Gourves, J.-P. Haelters, B. Corbel, N. Kervarec,
F. Michaud and L. Meijer
Vol 44
790, 742, 703 cm-1. Anal. Calcd. for C19H15BrN4 (379.25): C
60.17, H 3.99. Found: C 60.06, H 3.88.
4-(1-Benzyl-6-fluoro-1H-indol-3-yl)-2-pyrimidinamine (19k).
1484, 1463, 1210, 1194, 799 cm-1.
C15H15FN4 (270.30): C 66.65, H 5.59. Found: C 66.54, H 5.57.
4-[1-(3-Methyl-2-butenyl)-1H-indol-3-yl]-2-pyrimidinamine
1
(21a). Yellow prisms (50%); mp 168-170°C; H NMR (DMSO-
Anal. Calcd. for
1
Yellow prisms (75%); mp 167-169°C; H NMR (DMSO-d6): ꢀ
5.45 (s, 2H, CH2), 6.49 (brs, NH2), 6.95 (td, 1H, J=2.2, 8.8,
10.2, H5), 6.99 (d, 1H, J=5.3, H5'), 7.23 (dd, 1H, J=2.2, 10.2,
H7), 7.29-7.35 (m, 5H, Ph), 8.13 (d, 1H, J=5.3, H6'), 8.23 (s,
1H, H2), 8.64 (dd, 1H, J=8.8, 5.8, H4); 13C NMR (DMSO-d6):
ꢀ 49.5 (CH2), 97.1 (C7, d, J=26), 105.2 (C3), 109.0 (C5, d,
J=24), 113.6 (C5'), 122.7 (C3a), 124.0 (C4, d, J=10), 127.3
(2C, Ph), 127.7 (C, Ph), 128.7 (2C, Ph), 132.1 (C, Ph), 137.0
(C7a, d, J=12), 137.3 (C2), 157.2 (C6'), 159.1 (C6, d, J=235),
161.9/163.5 (C4'/C2'); IR (KBr): 3461, 3280, 3141, 2924,
1619, 1575, 1554, 1533, 1456, 1438, 1379, 1179, 930, 818,
712 cm-1. Anal. Calcd. for C19H15FN4 (318.35): C 71.68, H
4.75. Found: C 71.57, H 4.75.
d6): ꢀ 1.76 (s, 3H, CH3), 1.88 (s, 3H, CH3), 4.85 (d, 2H, J=6.9,
CH2), 5.42 (t, 1H, J=6.9, CH), 5.85 (brs, NH2), 6.99 (d, 1H,
J=5.3, H5'), 7.17 (m, 1H, H5/H6), 7.19 (m, 1H, H5/H6), 7.44 (d,
1H, J=8.0, H7), 8.06 (s, 1H, H2), 8.11 (d, 1H, J=5.3, H6'), 8.57
(d, 1H, J=7.9, H4); 13C NMR (DMSO-d6): ꢀ 18.0 (CH3), 25.4
(CH3), 44.1 (CH2), 105.3 (C3), 110.5/112.9 (C5'/C7),
119.8/120.6/122.1/122.6 (C4/C5/C6/CH), 126.0 (C2), 130.9
(C3a), 136.3/136.8 (C7a/C), 157.1/162.3/163.5 (C2'/ C4'/C6');
IR (KBr): 3464, 3276, 3135, 3052, 2959, 2936, 2911, 1625,
1613, 1572, 1533, 1473, 1457, 1440, 1392, 1379, 1326,
1211, 1170, 815, 747, 736 cm-1.
Anal. Calcd. for
C17H18N4 (278.35): C 73.35, H 6.52. Found: C 73.21, H 6.41.
4-[5-Bromo-1-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-pyrim-
idinamine (21j). Yellow prisms (51%); mp 166-168°C; 1H
NMR (acetone-d6): ꢀ 1.76 (s, 3H, CH3), 1.88 (s, 3H, CH3), 4.86
(d, 2H, J=6.9, CH2), 5.43 (t, 1H, J=6.9, CH), 5.87 (brs, NH2),
6.97 (d, 1H, J=5.4, H5'), 7.29 (dd, 1H, J=8.7, 1.9, H6), 7.36 (d,
1H, J=8.7, H7), 8.10 (s, 1H, H2), 8.11 (d, 1H, J=5.4, H6'), 8.81
(d, 1H, J=1.9, H4); 13C NMR (DMSO-d6): ꢀ 18.1 (CH3), 25.5
(CH3), 44.3 (CH2), 105.1 (C3), 112.6/114.35 (C5'/C7),
120.8/122.5/ 122.9/124.8 (C4/C5/C6/CH), 126.5 (C2), 133.1
(C3a), 135.9/ 136.4 (C7a/C), 155.7 (C6'), 162.5/162.7 (C2'/C4');
IR (KBr): 3484, 3294, 3146, 2943, 2851, 1634, 1577, 1537,
1487, 1466, 1423, 1401, 1385, 1359, 1334, 1212, 893, 809, 786
cm-1. Anal. Calcd. for C17H17BrN4 (357.25): C 57.15, H 4.80.
Found: C 57.03, H 4.79.
4-(1-Isopropyl-1H-indol-3-yl)-2-pyrimidinamine (20a). Yellow
1
prisms (41%); mp 189-191°C; H NMR (DMSO-d6): ꢀ 1.49 (d,
6H, J=6.5, CH3), 4.80 (m, 1H, J=6.5, CH), 6.42 (brs, NH2), 7.03
(d, 1H, J=5.2, H5'), 7.14 (m, 1H, H5/H6), 7.20 (m, 1H, H5/H6),
7.56 (d, 1H, J=8.0, H7), 8.09 (d, 1H, J=5.2, H6'), 8.32 (s, 1H,
H2), 8.58 (d, 1H, J=8.0, H4); 13C NMR (DMSO-d6): ꢀ 22.4 (2
CH3), 47.0 (CH), 105.5 (C3), 110.4 (C5'), 113.1 (C7),
120.7/122.1/122.7 (C4/C5/C6), 125.8/128.0 (C2/C3a), 136.5
(C7a), 156.1 (C6'), 162.8/163.0 (C4'/C2'); IR (KBr): 3313, 3168,
2980, 1645, 1562, 1519, 1460, 1407, 1365, 1306, 1213, 1177,
809, 743 cm-1. Anal. Calcd. for C15H16N4 (252.32): C 71.40, H
6.39. Found: C 71.33, H 6.31.
4-(5-Chloro-1-isopropyl-1H-indol-3-yl)-2-pyrimidinamine
1
(20c). Yellow prisms (42%); mp 181-183°C; H NMR (DMSO-
d6): ꢀ 1.49 (d, 6H, J=6.6, CH3), 4.81 (m, 1H, J=6.6, CH), 6.51
(brs, NH2), 7.04 (d, 1H, J=5.4, H5'), 7.21 (dd, 1H, J=8.8, 2.0,
H6), 7.61 (d, 1H, J=8.8, H7), 8.10 (d, 1H, J=5.4, H6'), 8.43 (s,
1H, H2), 8.65 (d, 1H, J=2.0, H4); 13C NMR (DMSO-d6): ꢀ 22.3
(2 CH3), 48.7 (CH), 105.1 (C5'), 112.7 (C3), 115.9 (C7),
122.1/123.3 (C4/C6), 126.7 (C5), 127.3 (C2), 134.9/135.5
(C7a/C3a), 143.0 (C2'), 155.9 (C6'), 168.3 (C4'); IR (KBr):
3320, 3167, 2974, 2931, 1656, 1563, 1517, 1463, 1209, 798, 789
cm-1. Anal. Calcd. for C15H15ClN4 (286.76): C 62.83, H 5.27.
Found: C 62.71, H 5.18.
Acknowledgment. Financial support by the “Canceropole
Grand Ouest” and the “Conseil Regional de Bretagne” are
gratefully acknowledged.
Supporting information available: experimental details and
analytical data for intermediates 2-5 and 7-16 are available, free
of charge, via e-mail at bernard.corbel@univ-brest.fr.
REFERENCES AND NOTES
4-(5-bromo-1-isopropyl-1H-indol-3-yl)-2-pyrimidinamine
(20f). Yellow prisms (41%); mp 193-195°C; H NMR (DMSO-
[1] (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-49. (b)
Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66,
1022-1037. (c) Mayer, A. M. S.; Hamann, M. T. Mar. Biotechnol. 2004,
6, 37-52. (d) Blunt, J. W.; Cop, B. R.; Munro, M. H. G.; Northcote, P.
T.; Prinsep, M. R. Nat. Prop. Rep. 2005, 22, 15-61.
1
d6): ꢀ 1.48 (d, 6H, J=6.7, CH3), 4.79 (m, 1H, J=6.7, CH), 6.50
(brs, NH2), 7.03 (d, 1H, J=5.3, H5'), 7.31 (d, 1H, J=8.7, H6),
7.56 (d, 1H, J=8.7, H7), 8.10 (d, 1H, J=5.3, H6'), 8.41 (s, 1H,
H2), 8.78 (s, 1H, H4); 13C NMR (DMSO-d6): ꢀ 22.5 (2 CH3),
47.5 (CH), 105.3 (C3), 112.5/112.6/113.8 (C5'/C7/C5), 124.8/
127.4 (C6/C4/C3a), 129.6 (C7a), 135.3 (C2), 155.7 (C2'), 162.7
(C4'/C6'); IR (KBr): 3308, 3163, 2974, 2929, 1655, 1570, 1516,
1462, 1410, 1367, 1287, 1208, 1178, 798, 789 cm-1. Anal.
Calcd. for C15H15BrN4 (331.21): C 54.39, H 4.56. Found: C
54.41, H 4.52.
[2] (a) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148-180.
(b) Pindur, U.; Lemster, T. Curr. Med. Chem. 2001, 8, 1681-1698.
[3] (a) Sakemi, S.; Sun, H. H. J. Org. Chem. 1991, 56, 4304-
4307. (b) Kawasaki, Y.; Yamashita, M.; Otha, S. J. Chem. Soc., Chem.
Commun. 1994, 2085-2086. (c) Kawasaki, Y.; Yamashita, M.; Otha, S.
Chem. Pharm. Bull. 1996, 44, 1831-1839. (d) Bartik, K.; Braekman, J.
C.; Daloze, D.; Stoller, C.; Huysecom, J.; Vandevyver, G.; Ottinger, R.
Can. J. Chem. 1987, 65, 2118-2121. (e) Braekman, J. C.; Daloze, D.;
Stoller, C. Bull. Soc. Chim. Belg. 1987, 96, 809-812. (f) Tsujii, S.;
Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S. S.; Lui, M.
S.; Pomponi, S. A.; Diaz, M. C. J. Org. Chem. 1988, 53, 5446-5453. (g)
Morris, S. A.; Andersen, R. J. Tetrahedron 1990, 46, 715-720. (h)
Kawasaki, Y.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Otha, S.
Heterocycles 1998, 48, 1887-1901.
4-(5-Fluoro-1-isopropyl-1H-indol-3-yl)-2-pyrimidinamine
1
(20j). Yellow prisms (45%); mp 154-156°C; H NMR (acetone-
d6): ꢀ 1.58 (d, 6H, J=6.7, CH3), 4.84 (m, 1H, J=6.7, CH), 5.94
(brs, NH2), 7.01 (m, 2H, H5', H7), 7.54 (dd, 1H, J=9.0, 4.4, H6),
8.10 (d, 1H, J=5.3, H6'), 8.31 (s, 1H, H2), 8.38 (dd, 1H, J=10.7,
2.6, H4); 13C NMR (DMSO-d6): ꢀ 22.4 (2 CH3), 47.5 (CH),
105.0 (C5'), 107.8 (C4/C6, d, J=25), 110.2 (C4/C6, d, J=26),
111.5 (C7, d, J=10), 112.8 (C3), 126.1 (C3a, d, J=9), 130.0 (C2),
133.2 (C7a), 155.0 (C6'), 158.1 (C5, d, J=233), 162.3/162.9
(C2'/C4'); IR (KBr): 3323, 3172, 2972, 1662, 1621, 1563, 1518,
[4] Vervoort, H. C.; Richards-Gross, S. E.; Fenical, W.; Lee, A.
Y.; Clardy, J. J. Org. Chem. 1997, 62, 1486-1490.
[5] (a) Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.;
Fujita, D.; Kiuchi, F.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 1527-
1529. (b) N'Diaye, Y.; Guella, G.; Chiasera, G.; Mancini, Y.; Pietra, F.

Jul-Aug 2007
Towards the Syntheses of N-H and N-Alkylated Derivatives of Meridianins
801
Tetrahedron Lett. 1994, 35, 4827-4830. (c) Guella, G.; Mancini, Y.;
N'Diaye, Y.; Pietra, F. Helv. Chim. Acta 1999, 77, 1203-1221.
[6] Bergmann, T.; Schories, D.; Steffan, B. Tetrahedron 1997,
53, 2055-2060.
[7] Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K.
L.; Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116-3118.
[8] Jakse, R.; Svete, J.; Stanovnik, B.; Golobic, A. Tetrahedron
2004, 60, 4601-4608.
[9] (a) Franco, L. H. ; De Kier Joffe, E. B. ; Puricelly, L. ;
Tatian, M. ; Seldes, A. M. ; Palermo, J. A. J . Nat. Prod. 1998, 61, 1130-
1132. (b) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro,
M. H. G.; Parkin, S.; Hope H. Tetrahedron 1994, 50, 3987-3992. (c)
Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.; Litaudon, M.;
Blunt, J. W.; Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994, 50,
3993-4000.
[10] Gompel, M.; Leost, M.; De Kier Joffe, E. B.; Puricelli, L.;
Hernandez Franco, L.; Palermo, J.; Meijer, L. Bioorg. Med. Chem. Lett.
2004, 14, 1703-1707.
[22] (a) Bejan, E.; Aït Haddou, H.; Daran, J. C.; Balavoine, G. G.
A. Synthesis 1996, 1012-1018; (b) Bredereck, H.; Effenberger, F.;
Botsch, H.; Rehn, H. Chem. Ber. 1965, 98, 1081-1086.
[23] Gray, N.; Detivaud, L.; Doerig, C.; Meijer, L. Current Med.
Chem. 1999, 6, 859-875.
[24] Pindur, U.; Lemster, T. Current Med. Chem. 2001, 8, 1681-
1698.
[25] (a) Carle, J. S.; Christophersen, C. J. Am. Chem. Soc. 1979,
101, 4012-4013. (b) Carle, J. S.; Christophersen, C. J. Org. Chem. 1980,
45, 1586-1589.
[26] Bacher, G.; Nickel, B.; Emig, P.; Vanhoefer, U.; Seeber, S.;
Shandra, A.; Klenner, T.; Beckers, T. Cancer Res. 2001, 61, 392-399.
[27] (a) Sundberg, R. J. “The chemistry of indoles”, Acad. Press,
New York, 1970. (b) Sundberg, R. J. “Comprehensive Heterocyclic
Chemistry”, Katrisky, A. R.; Rees, C. W.; Bird, C. W.; Cheeseman, G.
W. H. Eds, Pergamon, Oxford, 1984, vol. 4, 313-376. (c) Sundberg, R. J.
“indoles”, Acad. Press, San Diego CA, 1996.
[28] Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.;
Aquino, L. B. Org. Lett. 2001, 3, 1005-1007.
[29] Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915-
13928.
[11] Jiang, B.; Yang, C.-G. Heterocycles 2000, 53, 1489-1498.
[12] Fresneda, P. M.; Molina, P.; Bleda, J. A. Tetrahedron 2001,
57, 2355-2363.
[13] (a) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35,
1675-1735. (b) Stanovnik, B.; Steve, J. Chem. Rev. 2004, 104, 2433-
2480.
[30] Berger, J.; Flippin, L. A.; Greenhouse, R.; Jaime-Figueroa,
S.; Liu, Y.; Miller, A. K.; Putman, D. G.; Weinhardt, K. K.; Zhao, S.-H.;
US 5 958 934 (1999) and US 5 863 924 (1999).
[14] Bredereck, H.; Effenberger, F.; Butsch, H.; Rehn H. Chem.
Ber. 1965, 98, 1081-1086.
[15] Karpov A. S., Merkul E., Rominger F., Müller T. J. J. Angew.
Chem. Int. Ed .2005, 44, 6951-6956.
[16] Batcho, A. D.; Leimgruber, W. Org. Synth., coll. Vol. VII
1990, 34-41.
[17] Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 2757-2761.
[31] (a) Bredereck, H.; Simchen, G. Angew Chem. Int. Ed. 1963,
2, 738. (b) Bredereck, H.; Simchen, G.; Wahl, R. Chem. Ber. 1968, 101,
4048-4056.
[32] (a) Knockaert, M.; Grenngard, P.; Meijer, L. Trends
Pharmacol. Sci. 2002, 23, 417-425. (b) Hardcastle, I. R.; Golding, B. T.;
Griffin, R. J. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 325-348.
[33] Martinez, A.; Castro, A.; Dorronsoro, I.; Alonso, M. Medic.
Res. Rev. 2002, 22, 373-384.
[18] Illi, V. O. Synthesis 1979, 387-388.
[34] (a) Leclerc, S.; Garnier, M.; Hoesser, R.; Marko, D.; Bibb,
J. A.; Snyder, G. L.; Greengard, P.; Biernat, J.; Mandelkow, E.-M.;
Eisenbrand, G.; Meijer, L. J. Biol. Chem. 2001, 276, 251-260. (b)
Fabbro, D.; Ruetz, S.; Buchdunger, E.; Cowan-Jacob, S. W.;
Fendrich, G.; Liebetanz, J.; Mestan, J.; O'Reilly, T.; Traxler, P.;
Chaudhuri, B.; Fretz, H.; Zimmermann, J.; Meyer, T.; Caravatti, G.;
Furet, P.; Manley, P. W. Pharmacology & Therapeutics 2002, 93, 79-
98 (and ref. therein).
[35] (a) Furet, P. Curr. Med. Chem. Anticancer Agents 2003, 3,
15-23. (b) Fischer, P. M.; Endicott, J.; Meijer, L. Progr. Cell Cycle Res.
2003, 5, 235-248.
[36] Jiang, B.; Yang, C.-G.; Xiong, W.-N.; Wang, J. Bioorg. Med.
Chem. 2001, 9, 1149-1154.
[19] (a) Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50,
5451-5457. (b) Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J. J. Org.
Chem. 1989, 54, 4350-4356.
[20] (a) Brechbuehler, H.; Buchi, H.; Hatz, E.; Schreiber, J.;
Eschenmoser, A. Helv. Chim. Acta 1965, 48, 1746-1771. (b)
Vorbruggen, H. Angew. Chem. Internat. Ed. 1963, 2, 211-212 . (c)
Zemlicka, J. Coll. Czech. Chem. Commun. 1963, 28, 1060-1062. (d)
Stanovnik, B.; Tisler, M.; Hribar, A.; Barlin, G. B.; Brown, D. J. Aust. J.
Chem. 1981, 34, 1729-1738.
[21] (a) Middelton, R. W.; Monney, H.; Parrick, J. Synthesis 1984,
740-743. (b) Philips, K. D.; Horwitz, J. P. J. Org. Chem. 1975, 40, 1856-
1858.