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Concise Syntheses of Meridianins by Carbonylative Alkynylation and a Four-Component Pyrimidine Synthesis.

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Angewandte
Chemie
Multicomponent Reactions
DOI: 10.1002/anie.200501703
Concise Syntheses of Meridianins by
Carbonylative Alkynylation and a FourComponent Pyrimidine Synthesis**
Alexei S. Karpov, Eugen Merkul, Frank Rominger, and
Thomas J. J. Mller*
Dedicated to Professor Franz Effenberger
on the occasion of his 75th birthday
Pyrimidines constitute an important class of heterocycles,[1]
and many of the 2,4-substituted pyrimidines have been
recognized to be pharmaceutically highly active.[2] Particular
attention has focused on meridianins A–G (indole alkaloids
with a 2-aminopyrimidyl substituent which were recently
isolated from the Aplidium meridianum, an ascidian collected
in the South Atlantic; Scheme 1),[3] since they inhibit numerous protein kinases in a low micromolar range.[4] They are
Scheme 1. Meridianins and selected variolin alkaloids.
[*] Dr. A. S. Karpov, E. Merkul, Dr. F. Rominger, Prof. Dr. T. J. J. M-ller
Organisch-Chemisches Institut
Ruprecht-Karls-Universit2t Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+ 49) 6221-54-6579
E-mail: Thomas_J.J.Mueller@urz.uni-heidelberg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 850), by the Fonds der Chemischen Industrie,
and by the Dr.-Otto-RChm Ged2chtnisstiftung. We thank Dr. Dieter
Dorsch, Merck KGaA, Darmstadt, for providing screening data of
the meridianins and derivatives in kinase inhibition assays, BASF
AG for the generous donation of chemicals, and Michaela Schmitt
for experimental assistance.
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
related structurally to the variolins, alkaloids isolated from
the Antarctic sponge Kirkpatricka varialosa[5] which display
antitumor and antiviral activity. Among these alkaloids,
variolin B is the most biologically active compound. It
shows the inhibition of the growth of the P388 tumor cell
line and is also active against Herpes simplex and the polio
virus. In contrast, variolin D is completely inactive, emphasizing the importance of the 2-aminopyrimidine substituent for
the biological activity.
Three approaches to meridianins and variolins are currently known. While the first two routes apply Stille[6, 7] or
Suzuki couplings[8] of suitable indole stannanes or boronates
and halopyrimidine derivatives, the third more classical
approach is based upon a Bredereck synthesis of the 2aminopyrimidine moiety via b-enaminones.[9, 10] Just recently,
we have developed a straightforward consecutive one-pot
three-component access to pyrimidines by means of a
modified Sonogashira coupling of acid chlorides with terminal
alkynes and the subsequent transformation of alkynone
intermediates with amidinium salts.[11] Therefore, our diversity-oriented methodological approach to meridianin and
variolin alkaloids suggests the use of trimethylsilylynones
(TMS-ynones) as versatile synthetic equivalents of b-ketoaldehydes for the construction of the 2-aminopyrimidine ring
(Scheme 2). Here, we report on the development of carbon-
Scheme 2. Retrosynthetic analysis of meridianins and variolins.
ylative alkynylation to give TMS-alkynones, its application to
concise two-step syntheses of meridianins starting from 3iodoindole derivatives, first kinase inhibition tests of meridianins, and a new one-pot four-component syntheses of
pyrimidines.
Our initial route was based upon our established approach
to TMS-alkynones[11] starting from acid chlorides. But we
soon found that all attempts to prepare the required Nprotected indolyl acid chlorides by standard Friedel–Crafts
acylation[12] were less promising. Only the phenylsulfonyl
group could withstand these drastic, extremely acidic conditions; however, it was not really compatible for the
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subsequent coupling-cyclocondensation sequence. We therefore readjusted our retrosynthetic analysis and decided to
conceptually switch to a highly convergent carbonylative
coupling-cyclocondensation approach. A literature survey on
carbonylative alkynylation revealed that either high pressures
of carbon monoxide[13] are necessary, or for reactions under
normal pressure a twofold excess of relatively precious aryl
iodides is required.[14] Recently, Mori reported a practical
approach to ynones by carbonylative coupling using 2 equiv
of aqueous ammonia as a base.[15] However, our experience in
the preparation of TMS-ynones by Sonogashira coupling
suggested that we switch the base from ammonia to triethylamine in slight excess for the carbonylative Sonogashira
coupling.
Upon reaction of para-anisyl iodide (1 a) and 1-hexyne
(2 a) in THF at room temperature under 1 atm of carbon
monoxide (a CO-filled balloon attached to the reaction
vessel) and in the presence of 2 equiv of triethylamine and
catalytic amounts of [Pd(PPh3)2Cl2] and CuI the alkynone 3 a
was obtained in 82 % yield [Eq. (1)].
For carbonylative alkynylations with indoles tertbutoxycarbonyl(Boc)-protected 3-iodoindole derivatives 4
were identified to be the substrates of choice. Four representative indoles were prepared in a two-step sequence of
iodination (79–99 % yield) and subsequent Boc protection of
the indole nitrogen (72–86 % yield).[16, 17] However, the Pd
catalyst system had to be optimized for sufficient conversion
of the iodoindoles 4 into the desired TMS-alkynones 5
[Eq. (2), Table 1].
The structures of the TMS-alkynones 5 were unambiguously supported by spectroscopic (1H, 13C and DEPT, COSY,
HETCOR, and HMBC NMR experiments, IR, UV/Vis, mass
spectrometry) and combustion analyses, and in addition by an
X-ray structure analysis compound of 5 d (Figure 1).[18, 19]
The standard catalyst system (5 % [Pd(PPh3)2Cl2])
appeared to be most efficient only for the pyrrolopyridine
4 d (entry 7), whereas in all other cases a mixture of 0.05 equiv
of [Pd(PPh3)2Cl2] and 0.01 equiv of [Pd(dppf)Cl2] accelerated
the catalysis. However, when [Pd(dppf)Cl2] alone was applied
the catalyst, the desired alkynone became the minor product
and the formation of the TMS-ethynylindole dominated
(entry 4). To date, the mechanistic influence of this peculiar
catalyst cocktail on the selectivity of the carbonylative
alkynylation is not clear. Apparently the electronic nature
of the iodo substrates in conjunction with the Pd catalyst
precursor plays a key role and will be the subject of thorough
investigations. As a consequence of different rates in oxidative addition and from a methodological point of view, the
presence of bromo substituents (entries 3 and 5) does not
interfere with the regioselective carbonylative alkynylation at
the carbon–iodine bond. Most critical, however, was the
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
Angewandte
Chemie
application of only one equivalent of triethylamine as an HIscavenging base.
With this three-component carbonylative alkynylation in
hand, we set out to conclude the meridianin syntheses. First
attempts to conduct the meridianin syntheses in a consecutive
one-pot fashion failed, in particular, since the choice of the
ideal solvent system for the concluding cyclocondensation
step interferes with the carbonylative coupling step. Therefore, a separation of carbonylative
Table 1: Optimization of catalyst combinations for the carbonylative alkynylation of iodoindole
coupling and cyclocondensation
[a]
derivatives.
seemed to be reasonable. The
Entry
4
Catalyst system
5
Yield [%][b]
TMS-alkynones 5 were treated
with a 5 m aqueous solution of
1
2
guanidine
(2.5 equiv) and Na2CO3
R = R = H,
1
50
5 % [Pd(PPh3)2Cl2]
(1 equiv) at 80 8C in a 1:1 mixture of
X = CH (4 a)
tBuOH/CH3CN, and the desired
natural products 6 were isolated in
5a
68
2
4a
5 % [Pd(PPh3)2Cl2],
1 % [Pd(dppf)Cl2]
59–78 % yield (Scheme 3). Most
surprisingly, the pyrimidine formation occurs with the concomitant
R1 = Br, R2 = H,
5 % [Pd(PPh3)2Cl2],
cleavage of both TMS and Boc
3
68
X = CH (4 b)
1 % [Pd(dppf)Cl2]
groups. Interestingly, the use of
CH3CN/MeOH as a solvent mixture
5b
25[c]
4
4b
5 % [Pd(dppf)Cl2]
led to the predominant formation of
a double Michael addition product
of methanol.
5 % [Pd(PPh3)2Cl2],
R1 = H, R2 = Br,
This new two-step synthesis of
5
64
X = CH (4 c)
1 % [Pd(dppf)Cl2]
meridianins and related variolins is
not only apparently very general
but also extremely concise. If one
considers that the iodoindole deriv5 % [Pd(PPh3)2Cl2],
R1 = R2 = H,
atives can be prepared in another
39
6
X = N (4 d)
1 % [Pd(dppf)Cl2]
two steps from indole derivatives,
the overall yield of the four steps
7
4d
5 % [Pd(PPh3)2Cl2]
5d
63
[a] Reaction conditions: 3-iodoindole 4 (1.0 equiv), TMS-acetylene (1.5 equiv; 0.1 m in THF),
triethylamine (1 equiv), CuI (0.02 equiv), and the Pd catalyst were stirred at room temperature
for 48 h. [b] Yields refer to yields of compounds 5 isolated after flash chromatography on silica
gel to be 95 % pure as determined by NMR spectroscopy and elemental analysis and/or
HRMS. [c] 56 % of the alkynylation product.
Figure 1. X-ray crystal structure of 5 d; thermal ellipsoids at 50 %
probability. Selected bond lengths [I]: C10–N1 1.421, N1–C2 1.379,
C2–C3 1.353, C3–C15 1.462, C15–C16 1.460, C16–C17 1.203, C17–Si1
1.849.
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
Scheme 3. Cyclocondensation of TMS-alkynones 5 to give meridianins
and meridianin derivatives 6.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
starting from the indoles lies between 25 and 41 %. A striking
advantage over the b-enaminone pathway[9, 10] is that substituents other than H can be introduced readily at position 6
of the pyrimidine ring by choosing substituted alkynes.
Furthermore, the extremely mild conditions of TMS-alkynone formation are highly compatible with polar functional
groups. Polar substituents represent a significant drawback if
stannane and boronate intermediates are required.[6–8]
The structures of the meridiaTable 3: One-pot four-component carbonylative coupling–cyclocondensation synthesis of 2,4,6-trisubnins 6 a–c and variolin analogue 6 d
stituted pyrimidines 8 from aryl iodides ArI 1, alkynes HCCR3 2, and amidinium salts 7[a] (see
were unambiguously supported by
Equations (1) and (3)).
their 1H and 13C NMR spectra,
Entry 1
2
7
8
Yield [%][b]
which are in full agreement with
published data.[8, 10]
Since we were aware of the
biological activity of the natural2 a:
1 a: Ar = p1
51
7 a:[c] R4 = 2-thienyl
meridianines, we subjected the synR3 = nBu
MeOC6H4
thetic samples of compounds 6 to a
screening assay with protein kinases,[20] which play a key role in the
“metabolic syndrome” (hSGK1)
2 b:
and in oncogenesis. All four com2
1 b: Ar = 2-thienyl 3
56
7 b:[c] R4 = Me
R = Ph
pounds inhibit these tested kinases
at low micromolar and even nanomolar levels (Table 2).
Encouraged by the successful
total syntheses of meridianines, we
1 c: Ar = p7 c:[d] R4 = HN-2-CH3-53
2a
29
attempted the methodological
MeC6H4
O2NC6H3
advance to the one-pot four-component syntheses of pyrimidines by
a carbonylative coupling–cyclocondensation sequence. Reaction of
(hetero)aryl iodides 1 and terminal
1 d: Ar = p4
2b
7 b[c]
43
alkynes 2 in THF at room temperMeO2CC6H4
ature under 1 atm of carbon monoxide (a CO-filled balloon
attached to the reaction vessel)
and in the presence of 2 equiv of
1 e: Ar = ptriethylamine
and
catalytic
5
2a
7 a[c]
28[e]
NCC6H4
amounts of [Pd(PPh3)2Cl2] and
CuI for 48 h followed by addition
of the amidinium salts 7 in the
[a] Reaction conditions: A mixture of 1 (1.0 mmol), 2 (1.2 mmol), [Pd(PPh3)2Cl2] (0.05 mmol), CuI
presence of 2.5 equiv of sodium
(0.02 mmol), and NEt3 (2.0 mmol) (in THF (5 mL)) was stirred at room temperature for 48 h. Then 7
carbonate in acetonitrile/water
(1.2 equiv), Na2CO3 (2.5 equiv), water (0.5 mL), and CH3CN (5 mL) were added, and the reaction
gave the 2,4,6-trisubstituted pyrimixture was heated at reflux for 12–24 h. [b] Yields refer to yields of compounds 8 isolated after flash
midines 8 moderate to good yield
chromatography on silica gel and crystallization to be 95 % pure as determined by NMR spectroscopy
[Eq. (3), Table 3].
and elemental analysis. [c] Used as a hydrochloride. [d] Used as a nitrate. [e] Only 0.01 mmol of
The structures of the pyrimi[Pd(PPh3)2Cl2] without CuI was used as a catalyst; the reaction mixture was stirred for five days on the
dines 8 were unambiguously supfirst step.
Table 2: IC50 values [mm] of meridianins 6 a–c and the variolin analogue
6 d.
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Protein kinase
6a
6b
6c
6d
hSGK1
Tie-2
VEGFR2/KDR
PDGF-receptor b-kinase
Meck-EE kinase
IGF1-receptor tyrosine kinase
> 10
>1
>1
> 10
> 10
> 10
2.0
0.75
>1
> 10
2.3
> 10
4.5
1.6
>1
> 10
8.7
> 10
2.4
1.0
>1
> 10
> 10
> 10
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ported by spectroscopic (1H, 13C and DEPT NMR experiments, IR, UV/Vis, mass spectrometry) and combustion
analyses. It is noteworthy that this sequence proceeds
efficiently only for neutral or electron-rich aryl iodides 1
(entries 1 and 2). When electron-deficient aryl iodides were
examined, a 1:2 mixture of carbonylative and non-carbonylative products was isolated. On the other hand, attempts to
replace the aryl iodides with aryl bromides to increase the
selectivity led to the complete loss of reactivity, and only
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
Angewandte
Chemie
starting material was recovered. Finally, after considerable
experimentation, we found that stirring the electron-deficient
aryl iodide 1 e for 5 days with only 1 mol % of [Pd(PPh3)2Cl2]
and in the absence of CuI predominantly led to the formation
of carbonylative alkynylation product, which was subjected to
the cyclocondensation, providing the desired pyrimidine in
28 % yield (entry 5).
Although this pyrimidine synthesis based upon consecutive carbonylative alkynylation and cyclocondensation is
lower yielding than the synthesis starting from acid chlorides,[11] it still can be considered as a complementary approach
when acid-sensitive functionality cannot be tolerated.
In conclusion, we have developed concise syntheses of
naturally occuring meridianins and derivatives based upon
carbonylative alkynylation and subsequent cyclocondensation. Meridianins were found to inhibit “metabolic syndrome” and oncologically relevant protein kinases at low
micromolar and even nanomolar levels. Furthermore, we
have developed a novel one-pot four-component synthesis of
2,4,6-trisubstituted pyrimidines based upon a consecutive
carbonylative coupling–cyclocondensation sequence. Studies
addressing the methodological scope of this synthesis and
syntheses of other unknown analogs of meridianins and
variolins as well as thorough studies of the structure–activity
relationship are currently underway.
Experimental Section
5 b: In a Schlenk flask [Pd(PPh3)2Cl2] (35 mg, 0.05 mmol), [Pd(dppf)Cl2·CH2Cl2] (8 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol), Bocprotected iodo indole 4 b (422 mg, 1.00 mmol), and THF (5 mL) were
placed under nitrogen. Carbon monoxide was bubbled through the
solution for 5 min, and then TMS-acetylene (0.21 mL, 1.50 mmol) and
triethylamine (0.14 mL, 1.00 mmol) were added successively. The
reaction mixture became dark red and was stirred at room temperature for 48 h under 1 atm of carbon monoxide (balloon filled with
CO). The reaction mixture was then diluted with brine (20 mL) and
extracted with dichloromethane (5 L 20 mL). The combined organic
layers were dried with sodium sulfate, concentrated to dryness, and
subjected to column chromatography on silica gel (hexane/ethyl
acetate, 12:1) to give 5 b (287 mg; 68 %) as colorless crystals. M.p.
157–159 8C. 1H NMR (300 MHz, CDCl3): d = 0.32 (s, 9 H), 1.70 (s,
9 H), 7.47 (dd, J = 8.8 Hz, 1.8 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 8.36 (s,
1 H), 8.48 ppm (d, J = 1.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3): d =
0.7 (CH3), 28.0 (CH3), 86.1 (Cquat.), 97.0 (Cquat.), 101.3 (Cquat.), 116.5
(CH), 118.4 (Cquat.), 120.8 (Cquat.), 125.0 (CH), 128.1 (Cquat.), 128.9
(CH), 134.6 (Cquat.), 136.4 (CH), 148.4 (Cquat.), 171.5 ppm (Cquat.); EIMS (70 eV): m/z (%): 421 [M]+, 81Br, (7); 419 [M]+, 79Br, (5); 365
[M C4H9]+, 81Br, (58); 363 [M C4H9]+, 79Br, (49); 321
[M C4H9 CO2 H]+, 81Br, (100); 319 [M C4H9 CO2 H]+, 79Br,
(84); 306 (23); 304 (19); 57 [C4H9]+ (99); elemental analysis calcd (%)
for C19H22BrNO3Si (420.4): C 54.29, H 5.28, N 3.33, Br 19.01; found: C
54.00, H 5.33, N 3.37, Br 19.27.
6 b: To a solution of 5 b (185 mg, 0.44 mmol) in acetonitrile
(1.5 mL) was added in succession sodium carbonate (47 mg,
0.44 mmol), tert-butyl alcohol (1.5 mL), and a 5 m aqueous solution
of guanidine (0.22 mL, 1.1 mmol; prepared by dissolving guanidine
hydrochloride (9.55 g, 0.10 mol) in water (20 mL) and neutralizing
with sodium hydroxide (4.10 g, 0.10 mol). The reaction mixture was
stirred at 80 8C for 38 h. After conversion to the meridianin was
complete (TLC), brine was added and the mixture was extracted with
dichloromethane (3 L 20 mL). The combined organic layers were
dried with sodium sulfate, and after evaporation of the solvents in
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
vacuo the residue was chromatographed on deactivated silica gel
(ethanol/ammonia 9:1) with ethyl acetate/ethanol (9:1) to give 6 b
(93 mg; 73 %) as a light yellow solid (recrystallized from pentane).
M.p. 238–240 8C (103–106 8C).[10] 1H NMR ([D6]DMSO, 300 MHz):
d = 6.52 (br, 2 H, NH2), 7.00 (d, J = 5.1 Hz, 1 H, H-5’), 7.29 (dd, J = 1.8,
8.5 Hz, 1 H, H-6), 7.41 (d, J = 8.8 Hz, 1 H, H-7), 8.10 (d, J = 5.1 Hz,
1 H, H-6’), 8.26 (br, 1 H, H-2), 8.76 (d, J = 1.8 Hz, 1 H, H-4), 11.87 ppm
(br s, 1 H, NH); 13C NMR ([D6]DMSO, 75 MHz): d = 105.3 (CH),
113.3 (Cquat.), 113.4 (Cquat.), 113.8 (CH), 124.5 (CH), 124.6 (CH), 127.1
(Cquat.), 129.6 (CH), 135.8 (Cquat.), 157.2 (CH), 162.3 (Cquat.), 163.6 ppm
(Cquat.); elemental analysis calcd (%) for C12H9BrN4 (289.1): C 49.85,
H 3.14, N 19.38; found: C 50.10, H 3.24, N 18.87.
8 a: In a Schlenk flask [Pd(PPh3)2Cl2] (35 mg, 0.05 mmol), CuI
(4 mg, 0.02 mmol), para-iodoanisole (1 a; 234 mg, 1.00 mmol), and
THF (5 mL) were placed under nitrogen. Carbon monoxide was
bubbled through the solution for 5 min, and then hexyne 2 a (0.14 mL,
1.20 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added
successively. The reaction mixture became dark red and was stirred at
room temperature for 48 h under 1 atm of carbon monoxide (balloon
filled with CO). Then the suspension was treated with Na2CO3
(265 mg, 2.50 mmol), amidinium salt 7 a (195 mg, 1.20 mmol), water
(0.5 mL), and CH3CN (5 mL), and the reaction mixture was heated at
reflux for 24 h. After cooling to room temperature, the reaction
mixture was diluted with brine (20 mL) and extracted with dichloromethane (5 L 20 mL). The combined organic layers were dried with
sodium sulfate, concentrated to dryness, and subjected to column
chromatography on silica gel (hexane/ethyl acetate, 6:1) to give 8 a
(166 mg; 51 %) as a light yellow solid. M.p. 84–86 8C. 1H NMR
(CDCl3, 300 MHz): d = 0.97 (t, J = 7.4 Hz, 3 H), 1.38–1.56 (m, 2 H),
1.74–1.85 (m, 2 H), 2.80 (t, J = 7.9 Hz, 2 H), 3.87 (s, 3 H), 7.01 (d, J =
8.9 Hz, 2 H), 7.14 (dd, J = 5.0 Hz, 3.7 Hz, 1 H), 7.29 (s, 1 H), 7.45 (dd,
J = 5.0 Hz, 1.1 Hz, 1 H), 8.08 (dd, J = 3.7 Hz, 1.1 Hz, 1 H), 8.14 ppm (d,
J = 8.9 Hz, 2 H); 13C NMR (CDCl3, 75 MHz): d = 13.9 (CH3), 22.5
(CH2), 30.9 (CH2), 37.8 (CH2), 55.4 (CH3), 111.6 (CH), 114.1 (CH),
128.0 (CH), 128.5 (CH), 128.7 (CH), 129.2 (CH), 129.5 (Cquat.), 144.4
(Cquat.), 161.0 (Cquat.), 161.8 (Cquat.), 163.1 (Cquat.), 171.4 ppm (Cquat.);
EI-MS (70 eV): m/z (%): 324 [M]+ (2); 309 [M CH3]+ (4); 295
[M C2H5]+ (7); 282 [M C3H6]+ (100); elemental analysis calcd (%)
for C19H20N2OS (324.3): C 70.34, H 6.21, N 8.63, S 9.88; found: C
69.95, H 6.17, N 8.59, S 9.86.
Received: May 18, 2005
Published online: October 5, 2005
.
Keywords: C C coupling · carbonylation · heterocycles ·
multicomponent reactions · natural products
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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3-Iodoindoles were obtained in almost quantitative yields as
beige solids still containing traces of DMF and can be stored
without decomposition at 0 8C under nitrogen. However, it is
advisable to convert them directly to the more stable N-Bocprotected 3-iodoindoles 4, which were isolated as colorless solids
by column chromatography on neutral aluminium oxide (column
chromatography on silica gel leads to red color and accelerates
the decomposition).
Colorless crystal (polyhedron), dimensions 0.40 L 0.30 L
0.24 mm3, triclinic, P1̄, Z = 2, a = 9.8618(5), b = 10.0262(5), c =
11.1585(6) V,
a = 107.5620(10),
b = 103.5130(10),
g=
103.2620(10)8, V = 967.76(9) V3, 1 = 1.175 g cm 3, T = 200(2) K,
qmax = 26.398, MoKa radiation, l = 0.71073 V, 0.38 q scans with
CCD area detector, covering a whole sphere in reciprocal space,
9354 reflections measured, 3954 unique (Rint = 0.0282), 2889
observed (I > 2s(I)), intensities were corrected for Lorentz and
polarization effects, an empirical absorption correction was
applied using SADABS (program SADABS V2.03 for absorption correction, G. M. Sheldrick, Bruker Analytical X-rayDivision, Madison, Wisconsin, 2001) based on the Laue symmetry of the reciprocal space, m = 0.14 mm 1, Tmin = 0.95, Tmax =
0.97, structure solved by direct methods and refined against F2
with a full-matrix least-squares algorithm using the SHELXTLPLUS (5.10) software package (software package SHELXTL
V5.10 for structure solution and refinement, G. M. Sheldrick,
Bruker Analytical X-ray-Division, Madison, Wisconsin, 1997),
223 parameters refined, hydrogen atoms were treated using
appropriate riding models, goodness of fit 1.05 for observed
www.angewandte.org
reflections, final residual values R1(F) = 0.045, wR(F 2) = 0.110
for observed reflections, residual electron density 0.30 to
0.27 e V 3.
[19] CCDC-278205 (5 d) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[20] The kinase inhibition assays were carried out in collaboration
with Merck KGaA as described in S. P. Davies, H. Reddy, M.
Caivano, P. Cohen, Biochem. J. 2000, 351, 95.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 6951 –6956
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