Novel and efficient access to phenylamino-pyrimidine type protein kinase C inhibitors utilizing a Negishi cross-coupling strategy

Article abstract of DOI:10.1021/jo0505223

A novel, short, and efficient synthetic pathway to 3-{4-[2-(3- chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-propanol (CGP 60474) and a series of analogues was developed. The synthetic sequence consisted of a Negishi-type cross-coupling reaction i

Full text of DOI:10.1021/jo0505223

Novel and Efficient Access to Phenylamino-pyrimidine Type
Protein Kinase C Inhibitors Utilizing a Negishi Cross-Coupling
Strategy†
Peter Stanetty,* Gregor Hattinger, Michael Schnu¨rch, and Marko D. Mihovilovic
Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163,
A-1060 Vienna, Austria
peter.stanetty@tuwien.ac.at
Received March 15, 2005
A novel, short, and efficient synthetic pathway to 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-
pyridin-2-ylamino}-propanol (CGP 60474) and a series of analogues was developed. The synthetic
sequence consisted of a Negishi-type cross-coupling reaction in the key step followed by two
subsequent nucleophilic substitution reactions. This strategy represents a versatile and robust
protocol to access diverse analogues of the title compound for subsequent SAR studies as potential
phenylamino-pyrimidine type protein kinase C inhibitors.
SCHEME 1. Proteine Kinase Inhibitors of the
Phenylamino-pyrimidine Type
Introduction
The protein kinase C (PKC) enzyme family consists of
cytosolic serine/threonine kinases, and several represen-
tatives play a crucial role in signal transductions, cellular
proliferation, and differentiation.1 The individual PKC
subtypes show differences in the mode of activation and
in the specificity with respect to the natural protein
substrates.2,3 From animal tumor models it is already
known that various inhibitors of PKC show antitumor
activity.4,5 Therefore, the discovery and the development
of specific protein kinase inhibitors will have the poten-
tial to define more clearly the respective functional roles
of protein kinases in cells.
Phenylamino-pyrimidines such as 3-{4-[2-(3-chloro-
phenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-pro-
panol (CGP 60474)6 represent a promising class of
inhibitors of PKC with a high degree of selectivity versus
other serine/threonine and tyrosine kinases and show
competitive kinetics relative to ATP. Imatinib (Glivec),7
a tyrosine kinase inhibitor with high activity against
chronic myeloid leukemia (CML), was introduced to the
pharmaceutical market as the first commercial product
of this type very recently by Novartis (Scheme 1).8
In the literature the synthesis of CGP 60474 is reported
via a classical cyclization pathway (Scheme 2).6 Chlorine
is introduced into the 2-position of 4-acetylpyridine via
oxidation to the N-oxide and subsequent reaction with
† Dedicated to Prof. Fritz Sauter on the occasion of his 75th birth-
day.
(1) Nashizuka, Y. Nature 1984, 304, 693.
(2) Dekker, L. V.; Parker, P. J. Trends Biochem. Sci. 1994, 19, 73.
(3) Dekker, L. V.; McIntyre, P.; Parker, P. J. J. Biol. Chem. 1993,
268, 19498.
(4) Buchanan, J. G.; Sable, H. Z. In Selective Organic Transforma-
tions; Thyagarajan, B. S., Ed.; Wiley-Interscience: New York, 1972;
Vol. 2, pp 1-95.
(7) Zimmermann, J. Eur. Pat. Appl. 1993, EP 564409.
(5) Lyle, F. R. U.S. Patent 5,973,257, 1985; Chem. Abstr. 1985, 65,
2870.
(8) (a) Eberle, M.; Stierli, D.; Pillonel, C.; Ziegler, H. PCT Int. Appl.
2001, WO 2001093682. (b) Furet, P.; Zimmermann, J.; Capraro, H.
G.; Meyer, T.; Imbach, P. J. Comput.-Aided Mol. Des. 2000, 14, 403.
(6) Zimmermann, J. PCT Int. Appl. 1995, WO 9509853.
10.1021/jo0505223 CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/21/2005
J. Org. Chem. 2005, 70, 5215-5220
5215

Stanetty et al.
SCHEME 2. Classical Cyclization Route toward
CGP 60474a
SCHEME 3. Retrosynthetic Analysis of CGP 60474
(6c) and Its Isomer (12b)
a For reaction conditions see ref 6.
organyls) and a high tolerance of both methodologies
toward a wide range of functional groups.10 However,
there are also a number of limitations: tin organyls are
highly toxic, and many heterocyclic boronic acids11 could
not be successfully prepared, so far. In particular, boronic
acids of nitrogen heterocycles with two or more heteroa-
toms are only poorly covered in the literature.12 Conse-
quently, we favored a Negishi protocol10 that allowed us
to perform the preparation of the zinc organyl and the
coupling reaction in a one-pot reaction.
An important key intermediate within our strategy was
the pyridine zinc organyl 1a. It was obtained from
2-fluoro-4-iodopyridine 113 via lithium halogen exchange
with n-BuLi in the 4-position and addition of thoroughly
dried ZnCl2. Subsequent regioselective coupling with 2,4-
dichloropyrimidine 2 under Pd(PPh3)4 catalysis (0.005
equiv) in the 4-position14 afforded the desired pyridinyl-
pyrimidine 3 in 69% yield in a one-pot reaction (Scheme
4). In the initial experiment equimolar amounts of n-BuLi
and iodide 1 were used and the product was accompanied
by symmetrical bipyridinyl 4 (14%). This problem was
POCl3. The so obtained chloride III is then transformed
to IV by reaction with N,N-dimethylformamide dimethyl-
acetal. The second cyclization partner is prepared by
reaction of aniline derivatives with cyanamide and
equimolar amounts of HNO3 to give the corresponding
guanidine nitrates VI. Compounds IV and VI are then
cyclized to give VII, which led to the target compound
CGP 60474 (6c) via a nucleophilic exchange reaction.
This sequence leads to 6c in five steps with an overall
yield of 34% based on 4-acetylpyridine.
A drawback of this pathway is that for each variation
of the aniline part of the target molecule a corresponding
guanidine derivative has to be prepared. Even more
problems occur when variations of the heterocyclic ring
system are envisioned, as a new synthetic strategy has
to be developed in most cases.
In the present paper we report a new, short, and
efficient synthesis of CGP 60474 based on a Pd-assisted
cross-coupling reaction, which was also applied to the
synthesis of a series of various new analogues and
isomers of the title compound.9 These synthetic targets
represent useful models for SAR studies and antiprolif-
erative activity, and the methodology can also be ex-
tended easily to the synthesis of various other structural
analogues.
(10) (a) Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., de Meijere, A., Eds.; John Wiley & Sons:
Hoboken, NJ, 2002; Vol. 1. (b) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633. (c) Stille, J. K. Angew. Chem. 1986, 98,
504.
(11) Tyrrell, E.; Brookes, P. Synthesis 2003, 469.
Results and Discussion
(12) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemis-
try-A Guide for the Synthetic Chemist; Pergamon Press: Oxford, 2000.
(b) Bianchi, G.; Cogoli, A.; Gru¨nanger, P. J. Organomet. Chem. 1966,
6, 598. (c) Davies, M. W.; Wybrow, R. A. J.; Johnson, C. N.; Harrity, J.
P. A. Chem. Commun. 2001, 17, 1558. (d) Fischer, F. C.; Havinga, E.
Recl. Trav. Chim. Pays-Bas 1965, 84, 439. (e) Coudret, C. Synth.
Commun. 1996, 26, 3543. (f) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org.
Chem. 1993, 58, 2201. (g) Liao, T. K.; Podrebarac, E. G.; Cheng, C. C.
J. Am. Chem. Soc. 1964, 86, 1869. (h) Gronowitz, S.; Hornfeldt, A.-B.;
Kristjansson, V.; Musil, T. Chem. Scr. 1986, 26, 305.
As a key step for the synthesis of the target compounds
depicted in Scheme 3, a Pd-catalyzed cross-coupling
reaction was envisioned followed by two subsequent
nucleophilic substitution reactions.
The Suzuki-Miyaura and the Stille reaction are the
most common cross-coupling methods because of certain
advantages such as easy access and relatively high
stability of the reagents (boronic acids/esters or tin
(13) (a) Estel, L.; Marsais, F., Queguiner, G. J. Org. Chem. 1988,
53, 2740. (b) Rocca, P.; Chochennec, C.; Marsais, F.; Thomas-dit-
Dumont, L.; Mallet, M.; Godard, A.; Queguiner, G. J. Org. Chem. 1993,
58, 7832.
(14) (a) Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
(b) Littke, A. F.; Fu, G. C. Angew. Chem. 2002, 114, 4350.
(9) Hattinger, G.; Stanetty, P.; Eberle, M. UK Pat. Appl. 2002, GB
2369359.
5216 J. Org. Chem., Vol. 70, No. 13, 2005

Phenylamino-pyrimidine Type Protein Kinase C Inhibitors
SCHEME 4. Negishi Cross-Coupling for the
Formation of Intermediate 3a
SCHEME 6. Sequential Nucleophilic Exchange
Reactions on 3a
a Reagents and conditions: (a) n-BuLi, ZnCl2, THF; (b) 2,4-
dichloropyrimidine, Pd(PPh3)4, reflux, THF, 4 h.
SCHEME 5. Nucleophilic Exchange Reactions on
3a
a Reagents and conditions: (a) HCl, acetone/water 4/1, reflux,
3 h; (b) 2 N aqueous HCl, reflux, 45 min; (c)-(e) see Table 1.
a Reagents and conditions: (a) 3-aminopropanol (1.4 equiv),
DMF, reflux, 1.5 h; (b) 3-aminopropanol (excess), 160 °C, 16 h.
with an aryl-containing amine (benzylamine and anilines)
followed by a subsequent conversion with 3-aminopro-
panol. In the case of benzylamine the nucleophilic
exchange reaction led to the desired compound in good
yield (72% 5b). Because of the low nucleophilicity,
reaction with aniline required prior deprotonation by
n-BuLi to finally yield the desired compound 5c in 44%
yield, accompanied by a number of not identified decom-
position products. We therefore looked for an alternative
method to improve the yield.
Instead of increasing the reactivity of the N-nucleophile
the reactivity of the aromatic center in 3 can be increased
by protonation of the ring nitrogen. Although in the
presence of catalytic amounts (0.1 equiv) of HCl under
aqueous conditions only traces of the desired product
were obtained, addition of HCl in equimolar quantities
was crucial for good conversion, ultimately leading to 51%
of 5c. With 3-chloroaniline product 5d was formed in 53%
yield accompanied by 19% of a byproduct 7. The identity
of 2-pyridinone 7 was confirmed by acid-catalyzed hy-
drolysis of the fluorine atom in a control experiment:
when 5d was refluxed in aqueous HCl, 7 was obtained
in 75% yield (Scheme 6). The method of choice to avoid
this side reaction was finally found in using a catalytic
amount of p-TSA in dry dioxane, which led to 5d in 89%
yield (Table 1).
The introduction of the basic side chain was finally
accomplished by heating the corresponding intermediates
(5b-d) in an excess of 3-aminopropanol and led to the
desired products (6b-c).
In a final experiment we also successfully performed
the nucleophilic exchange reactions sequentially as a one-
pot reaction. Compound 3 was first refluxed with 3-
chloroaniline (1.5 equiv) and p-TSA (0.85 equiv) in dry
dioxane for 5 h, then the solvent was evaporated, 3-
aminopropanol was added, and the reaction mixture was
refluxed for another 4 h. After workup and purification
the desired compound 6c (CGP 60474) was obtained in
81% overall yield.
solved by using a slight excess of n-BuLi (1.05 equiv),
and 3 was obtained in an excellent 90% yield with only
traces of 4.
Alternatively, the cross-coupling reaction can be car-
ried out under microwave conditions facilitating the
reaction within 5 min. In contrast to the thermal condi-
tions the 2-chloro atom was also active enough for cross-
coupling to form 2,4-bis-(2-fluoropyridin-4-yl)-pyrimi-
dine.15
According to our strategy two consecutive nucleophilic
substitution steps are required to yield the desired target
compounds. A bibliographic investigation indicated that
the relative reaction rate in a nucleophilic exchange
reaction of 2-chloropyrimidine is about 8 orders of
magnitude higher than that in 2-chloropyridine.16 As no
data for exchange rates of 2-chloro and 2-fluoropyridine
are available, we compared those reported for various
chloro- and fluoronitrobenzenes. Thus, exchange rates for
the corresponding fluoro compound in each case were
approximately 3 orders of magnitude higher.17 Conse-
quently, the Cl atom in 3 should be exchanged more
easily than F, although the difference in reactivity is
decreased. To confirm the above hypothesis, a control
experiment using 3-aminopropanol was carried out and
compound 5a was obtained in 66% yield, as expected
(Scheme 5). Under extended reaction time with an excess
of 3-aminopropanol at 160 °C we could demonstrate
successful substitution of the fluorine atom as well. After
workup and purification we obtained the expected prod-
uct 6a in 68% yield.
To establish the correct substitution pattern the first
nucleophilic exchange reaction requires transformation
(15) Stanetty, P.; Schnu¨rch, M.; Mihovilovic, M. D. Synlett 2003,
12, 1862.
(16) Chan, T. L.; Miller, J. Aust. J. Chem. 1967, 20, 1595.
(17) (a) Bunnett, J. F.; Garbisch, E. W.; Pruitt, K. M. J. Am. Chem.
Soc. 1957, 79, 385. (b) Parker, R. E.; Read, T. O. J. Chem. Soc. 1962,
9. (c) Suhr, H. Chem. Ber. 1964, 97, 3268. (d) Bolto, B. A.; Miller, J.
Aust. J. Chem. 1956, 9, 74.
J. Org. Chem, Vol. 70, No. 13, 2005 5217

Stanetty et al.
TABLE 2. Nucleophilic Exchange Reactions of 9
TABLE 1. Nucleophilic Exchange Reactions of 3
R
R’
compound
conditions
yield (%)
R
R′
compound
yield (%)
(CH2)3OH
Bn
5a
5b
5c
5c
5d
5d
6a
6b
6c
a
a
b
c
66
72
44
51
53
89
68
75
88
Ph
11a
11b
11c
12a
12b
12c
12d
75
3-Cl-Ph
3-CF3-Ph
Ph
85a
69a
87
Ph
Ph
OH
3-Cl-Ph
3-Cl-Ph
(CH2)3OH
Bn
c
3-Cl-Ph
3-CF3-Ph
3-Cl-Ph
OH
97
d
e
e
e
OH
N(CH3)2
92
(CH2)3OH
(CH2)3OH
(CH2)3OH
84
a Isolated as hydrochloride.
3-Cl-Ph
a DMF, amine, reflux. b n-BuLi, aniline, -30 °C to reflux.
c Aniline derivative, HCl, acetone/water, reflux. d 3-Chloroaniline,
p-TSA, dry dioxane, reflux. e 3-Aminopropanol, reflux.
compound was obtained in five steps with an overall yield
of 64% (2-fluoro-3-iodopyridine was prepared according
to the literature13a but in an improved 90% yield, 2-fluoro-
4-iodopyridine13b in an improved 98% yield) compared to
34% overall yield by the established method (also five
steps). The major advantage compared to the previous
strategy is the flexibility of the presented protocol giving
access to a large variety of derivatives and isomers.
SCHEME 7. Formation of Isomers of CGP 60474a
Experimental Section
General Procedure 1. Negishi Cross-Coupling Reac-
tion (Representative Procedure for the Preparation of
3). 4-Iodo-2-fluoropyridine 1 (15.52 g, 69.60 mmol, 1 equiv) was
dissolved in dry THF (150 mL) and cooled to -70 °C. Then
n-BuLi (73.08 mmol, 1.05 equiv) was added and the reaction
mixture was stirred at -70 °C for 20 min. Subsequently, dry
ZnCl2 (10.44 g, 76.61 mmol, 1.1 equiv) was added as a solution
in dry THF (60 mL) keeping the temperature below -60 °C.
The reaction mixture was then warmed to room temperature,
Pd(PPh3)4 (0.40 g, 0.35 mmol, 0.005 equiv) and 2 (7.26 g, 48.73
mmol, 0.75 equiv in 100 mL dry THF) were added, and the
reaction mixture was refluxed until complete conversion.
Workup 1. The reaction mixture was poured onto a 10%
aqueous EDTA solution, basified with saturated aqueous
Na2CO3 solution, and extracted with CH2Cl2. The crude
material was recrystallized or purified by flash column chro-
matography (FCC).
a Reagents and conditions: 4,6-dichloropyrimidine, Pd(PPh3)4,
reflux, THF; (b) aniline derivative, HCl, acetone/water, reflux; (c)
amine, reflux.
Workup 2. Most of the solvent was evaporated and the
residue was poured onto water. The resulting precipitate was
filtered and the crude material was again recrystallized or
purified by flash column chromatography (FCC).
Synthesis of the Isomeric System 12. The cross-
coupling reaction conditions optimized for the synthesis
of 3 were applicable also for the formation of the isomeric
biaryl intermediate 9, which in turn led to isomeric target
compounds 12a-d (Scheme 7).
When 4,6-dichloropyrimidine 8 was coupled with the
organyl 1a the desired compound 9 (40%) was the major
reaction product but accompanied by bis-coupled material
10 (30%).
Similar to conversion of compound 3 nucleophilic
attack by aniline derivatives led to substitution of the
pyrimidine-chlorine prior to the pyridine-fluorine. When
aqueous HCl was used for this transformation the
reaction was accompanied by formation of byproduct 13
(15% yield) similar to compound 7. However in a mixture
of acetone and water the nucleophilic substitution pro-
gressed smoothly to the expected products 11a-c (Scheme
7). The subsequent substitution of the fluorine atom gave
the desired isomeric analogues (12a-d) to CGP 60474
in good to excellent yields (Table 2).
2-Chloro-4-(2-fluoropyridin-4-yl)pyrimidine, 3.18 Pre-
pared by general procedure 1. Mp 157-159 °C; 90% (9.17 g,
43.75 mmol, beige crystals); workup 1; FCC PE/EtOAc 10:1.
Anal. Calcd for C9H5ClFN3: C, 51.57; H, 2.40; N, 20.05.
Found: C, 51.78; H, 2.33; N, 20.01.
2,2′-Difluoro-[4,4′-bipyridine], 4.18 Prepared via general
procedure 1. Mp 155-200 °C (decomp); 5% (0.33 g, 1.72 mmol,
colorless crystals); workup 1; FCC PE/EtOAc 10:1. Anal. Calcd
for C10H6F2N2: C, 62.50; H, 3.15; N, 14.58. Found: C, 62.21;
H, 3.29; N, 14.33.
3-[[4-(2-Fluoropyridin-4-yl)-2-pyrimidin-4-yl]amino]-
propanol, 5a. Substrate 3 (0.32 g, 1.53 mmol, 1 equiv) was
refluxed with 1.4 equiv (0.16 g, 2.13 mmol) of 3-aminopropanol
for 1.5 h in dry DMF (20 mL). The reaction mixture was then
poured onto water and extracted with EtOAc. The crude
material was purified by FCC PE/EtOAc 10:1 to yield 66%
1
(0.25 g, 1.01 mmol, yellow crystals) 5a. Mp 123-124 °C; H
NMR (d6-DMSO, 200 MHz) δ 1.72 (quin, 3J ) 7 Hz, 2H), 3.39-
3
3
3.57 (m, 4H), 4.49 (t, J ) 7 Hz, 1H), 7.28 (d, J ) 5 Hz, 1H),
3
3
7.38 (t, J ) 7 Hz, 1H), 7.79 (s, 1H), 8.00 (d, J ) 5 Hz, 1H),
8.39 (d, 3J ) 5 Hz, 1H), 8.47 (d, 3J ) 5 Hz, 1H); 13C NMR (d6-
DMSO, 50 MHz) δ 32.1 (t), 38.1 (t), 58.7 (t), 106.1 (d), 106.5
2
4
3
(d, JCF ) 46 Hz), 119.2 (d, JCF ) 4 Hz), 148.4 (d, JCF ) 15
Conclusion
An efficient and versatile synthesis for CGP 60474 (6c)
was developed. Starting from 2-fluoropyridine the target
(18) Hametner, C.; Hattinger, G.; Ro¨hrling, J.; Fro¨hlich, J.; Stanetty,
P.; Mihovilovic, M. D. Magn. Reson. Chem. 2001, 39, 417.
5218 J. Org. Chem., Vol. 70, No. 13, 2005

Phenylamino-pyrimidine Type Protein Kinase C Inhibitors
3
1
Hz), 150.6 (d, JCF ) 8 Hz), 159.9 (d), 162.6 (s), 164.0 (d, JCF
) 233 Hz). Anal. Calcd for C12H13N4O: C, 58.06; H, 5.28; N,
22.57. Found: C, 57.71; H, 5.33; N, 22.62.
3-[[4-[2-(3-Hydroxypropylamino)-pyridin-4-yl]-2-pyri-
midin-4-yl]amino]-propanol, 6a. Substrate 3 (0.29 g, 1.40
mmol, 1 equiv) was heated in 3-aminopropanol (5 mL) to 160
°C for 16 h. The reaction mixture was poured onto water and
extracted with EtOAc. Recrystallization from EtOAc gave 68%
(0.29 g, 0.96 mmol, yellow crystals) of 6a. Mp 169-172 °C; 1H
NMR (d6-DMSO, 200 MHz) δ 1.65-1.80 (m, 4H), 3.28-3.39
(m, 4H), 3.43-3.57 (m, 4H), 4.50 (bs, 2H), 6.58-6.70 (m, 2H),
7.03 (d, J ) 5 Hz, 1H), 7.10 (s, 1H), 7.19 (t, J ) 7 Hz, 1H),
8.07 (d, 3J ) 5 Hz, 1H), 8.39 (d, 3J ) 5 Hz, 1H); 13C NMR (d6-
DMSO, 50 MHz) δ 32.2 (d), 32.4 (d), 38.1 (d), 58.7 (d), 58.8 (d),
105.2 (d), 105.7 (d), 108.6 (d), 145.0 (s), 148.3 (d), 159.2 (d),
159.7 (s), 162.6 (s). Anal. Calcd for C15H21N5O2: C, 59.39; H,
6.98; N, 23.09. Found: C, 59.67; H, 7.09; N, 22.79.
General Procedure 3. Introduction of the Aminopro-
panol Side Chain (6b, 6c, 12a-c). The corresponding
substrate was heated in 3-aminopropanol (10 mL for 0.5 g) to
150-160 °C until completion. The reaction mixture was cooled
to 0 °C and the product was precipitated by addition of water.
The residue was filtered, and the product was washed with
cold water and dried in vacuo at 50 °C. In some cases the
precipitate could not be filtered and the product was isolated
by extraction with EtOAc and subsequent purification by
column chromatography.
N-(Phenylmethyl)-4-(2-fluoropyridin-4-yl)-2-pyrimi-
dinamine, 5b. Substrate 3 (1.51 g, 7.20 mmol, 1 equiv) and
benzylamine (1.00 g, 9.33 mmol, 1.3 equiv) were heated in dry
DMF (30 mL) to 150 °C for 1 h. The reaction mixture was
poured onto water and the resulting precipitate filtered and
dried in vacuo at 50 °C to give 72% (1.45 g, 5.17 mmol, yellow
crystals) of 5b. Mp 167-169 °C; recrystallized from EtOAc;
1H NMR (d6-DMSO, 200 MHz) δ 4.61 (d, 3J ) 7 Hz, 2H), 7.22
3
3
3
3
3
(t, J ) 8 Hz, 1H), 7.30 (d, J ) 5 Hz, 1H), 7.31 (t, J ) 8 Hz,
2H), 7.32-7.42 (m, 2H), 7.75 (s, 1H), 7.92-8.05 (m, 2H), 8.38
(d, 3J ) 5 Hz, 1H,), 8.48 (d, 3J ) 5 Hz, 1H); 13C NMR (d6-
DMSO, 50 MHz) δ 44.1 (d), 106.5 (d), 106.6 (d, 2JCF ) 39 Hz),
119.2 (d, 4JCF ) 4 Hz), 126.5 (d), 127.1 (d), 128.2 (d), 140.3 (s),
148.4 (d, 3JCF ) 15 Hz), 150.4 (d, 3JCF ) 8 Hz), 160.1 (d), 162.5
1
(s), 164.0 (d, JCF ) 233 Hz). Anal. Calcd for C16H13FN4: C,
68.56; H, 4.67; N, 19.99. Found: C, 68.31; H, 4.87; N, 19.75.
General Procedure 2. Nucleophilic Substitution un-
der Acidic Conditions (5c, 11a-c). The corresponding
substrate was mixed with the aniline derivative (1.05 equiv)
and concentrated HCl (1.1 equiv) in a mixture of acetone/water
(4/1) and refluxed for 3 h. The reaction mixture was cooled
and the formed precipitate was filtered and washed with
water. The product (as hydrochloride) was dried in vacuo at
50 °C. Alternatively, the product can also be isolated as free
amine; therefore the reaction mixture is basified with aqueous
NaHCO3 solution and again the resulting precipitate filtered,
washed with water, and dried in vacuo at 50 °C. If necessary
the crude material was purified by flash column chromatog-
raphy.
3-[[4-[2-[(Phenylmethyl)amino]pyrimidin-4-yl]-pyridin-
2-yl]amino]-propanol, 6b. Prepared via general procedure
3. Mp 152-154 °C; 75% (1.24 g, 3.70 mmol, yellow crystals);
precipitated from water; 1H NMR (d6-DMSO, 200 MHz) δ 1.70
3
3
(quin, J ) 7 Hz, 2H), 3.33 (q, 2H, J ) 2 Hz), 3.50 (q, J ) 7
3
Hz, 2H), 4.50-4.64 (m, 3H), 6.68 (t, J ) 7 Hz, 1H.), 7.02 (d,
3J ) 5 Hz, 1H), 7.06 (d, J ) 5 Hz, 1H), 7.12 (s, 1H), 7.20-
3
7.41 (m, 5H), 7.84 (t, 3J ) 7 Hz, 1H.), 8.07 (d, 3J ) 5 Hz, 1H),
8.38 (d, J ) 5 Hz, 1H); 13C NMR (d6-DMSO, 50 MHz) δ 32.3
3
4-(2-Fluoropyridin-4-yl)-N-phenyl-2-pyrimidin-
amine, 5c. Prepared via general procedure 2. Mp 180-183
°C; 51% (0.13 g, 0.49 mmol, yellow crystals); FCC PE/EtOAc
5:1. Alternative procedure under basic conditions: aniline (0.14
g, 1.5 mmol, 1.1 equiv) in dry THF (20 mL) was deprotonated
with n-BuLi (0.63 mL, 1.50 mmol, 1.1 equiv) at -30 °C under
nitrogen atmosphere. The reaction mixture was stirred for 30
min before 3 (0.28 g, 1.34 mmol, 1 equiv in 5 mL dry THF)
was added at that temperature. The reaction mixture was
warmed to room temperature and refluxed for 18 h. The
solvent was subsequently evaporated and the crude material
purified by FCC (PE/EtOAc 5:1) to give 44% (0.16 g, 0.60
mmol). 1H NMR (d6-DMSO, 200 MHz) δ 7.00 (t, 3J ) 8 Hz,
(t), 38.1 (t), 44.1 (t), 58.7 (t), 105.0 (d), 106.1 (d), 108.6 (d), 126.5
(d), 127.2 (d), 128.2 (d), 140.5 (s), 144.9 (s), 148.3 (d), 159.4
(d), 159.7 (s), 162.5 (s). Anal. Calcd for C19H21N5O: C, 68.04;
H, 6.31; N, 20.88. Found: C, 67.74; H, 6.43; N, 20.72.
3-[[4-[2-[(3-Chlorophenyl)amino]pyrimidin-4-yl]pyri-
din-2-yl]amino]-propanol, 6c. Prepared via general proce-
dure 3. Mp 144-147 °C, 88% (0.32 g, 0.90 mmol, yellow
crystals); precipitated from water; 1H NMR (d6-DMSO, 200
3
3
MHz) δ 1.72 (quin, J ) 7 Hz, 2H), 3.33 (q, J ) 7 Hz, 2H),
3.52 (q, 3J ) 7 Hz, 2H), 4.51 (t, 3J ) 7 Hz, 1H), 6.72 (t, 3J ) 7
3
4
3
Hz, 1H.), 7.02 (dd, J ) 8 Hz, J ) 2 Hz, 1H), 7.12 (d, J ) 5
3
3
Hz, 1H), 7.13 (s, 1H), 7.34 (t, J ) 8 Hz, 1H), 7.38 (d, J ) 5
3
4
4
3
3
Hz, 1H), 7.78 (dd, J ) 8 Hz, J ) 2 Hz, 1H), 8.03 (t, J ) 2
Hz, 1H), 8.12 (d, 3J ) 5 Hz, 1H), 8.65 (d, 3J ) 5 Hz, 1H), 9.95
(s, 1H.); 13C NMR (d6-DMSO, 50 MHz) δ 32.2 (t), 38.2 (t), 58.7
(t), 104.9 (d), 108.6 (d), 108.9 (d), 117.1 (d), 118.0 (d), 120.9
(d), 130.1 (d), 133.0 (s), 142.0 (s), 144.5 (s), 148.6 (d), 159.4
(d), 159.7 (s), 159.9 (s), 162.7 (s). Anal. Calcd for C18H18ClN5O:
C, 60.76; H, 5.10, N, 19.68. Found: C, 60.51; H, 5.09; N;
19.61.
1H), 7.32 (t, J ) 8 Hz, 2H), 7.56 (d, J ) 5 Hz, 1H), 7.80 (d,
3J ) 8 Hz, 2H), 7.82 (s, 1H), 8.03 (d, J ) 5 Hz, 1H), 8.42 (d,
3
3J ) 5 Hz, 1H), 8.68 (d, 3J ) 5 Hz, 1H), 9.82 (s, 1H); 13C NMR
(d6-DMSO, 50 MHz) δ 106.8 (d, 2JCF ) 39 Hz), 108.8 (d), 119.2
(d), 119.3 (d, 4JCF ) 4 Hz), 121.8 (d), 128.5 (d), 140.1 (s), 148.6
3
3
(d, JCF ) 15 Hz), 150.2 (d, JCF ) 8 Hz), 159.9 (d), 160.1 (s),
160.2 (s), 164.0 (d, JCF ) 234 Hz).
1
N-(3-Chlorophenyl)-4-(2-fluoropyridin-4-yl)-2-pyrim-
idinamine, 5d. Substrate 3 (0.34 g, 1.62 mmol, 1 equiv) was
refluxed in dioxane with 3-chloroaniline (0.26 g, 2.04 mmol,
1.26 equiv) and p-TSA (0.26 g, 1.37 mmol, 0.85 equiv) for 5 h.
The reaction mixture was concentrated in vacuo, poured onto
water, and basified with saturated aqueous NaHCO3 solution.
The resulting precipitate was filtered and dried in vacuo at
50 °C to give 89% (0.43 g, 1.43 mmol, yellow crystals) 5d
without further purification. Mp 188-190 °C. Alternatively
5d was prepared via general procedure 2 to yield 53% (0.83 g,
Formation of 6c via One-pot Reaction. Substrate 3 (0.98
g, 4.68 mmol), 3-chloroaniline (0.89 g, 6.98 mmol) and p-TSA
(0.76 g, 4.00 mmol) were refluxed for 5 h in dry dioxane. The
solvent was then evaporated, and an excess of 3-aminopro-
panol was added and heated for 4 h to 170 °C. The reaction
mixture was then cooled to room temperature, water was
added, and the mixture was basified with saturated aqueous
NaHCO3 solution. The resulting precipitate was filtered and
dried and the crude material was recrystallized from EtOAc.
Yield: 81% (1.35 g, 3.79 mmol) yellow crystals.
1
3
2.76 mmol). H NMR (d6-DMSO, 200 MHz) δ 7.05 (d, J ) 8
3
3
Hz, 1H), 7.35 (t, J ) 8 Hz, 1H), 7.62 (d, J ) 5 Hz, 1H), 7.70
(d, 3J ) 8 Hz, 1H), 7.83 (s, 1H), 8.00-8.10 (m, 2H), 8.45 (d, 3J
4-[2-[Amino-(3-chlorophenyl)]pyrimidin-4-yl]pyridin-
2(1H)-one, 7. Mp 286-288 °C; 5e (0.04 g, 0.13 mmol, 1 equiv)
was refluxed for 45 min in 2 N aqueous HCl (15 mL). The
reaction mixture was cooled and basified with saturated
aqueous NaHCO3 solution. The formed precipitate was filtered
and the product was dried in vacuo at 50 °C to give 75% (0.03
g, 0.10 mmol, yellow crystals) of 7 (also formed in 22% yield
as byproduct during the formation of 5e under aqueous
) 5 Hz, 1H), 8.72 (d, J ) 5 Hz, 1H), 10.05 (s, 1H); 13C NMR
3
(d6-DMSO, 50 MHz) δ 106.8 (d, 2JCF ) 39 Hz), 109.3 (d), 117.2
(d), 118.2 (d), 119.2 (d, 4JCF ) 4 Hz), 121.1 (d), 130.0 (d), 132.9
3
3
(s), 141.7 (s), 148.5 (d, JCF ) 15 Hz), 149.9 (d, JCF ) 8 Hz),
1
159.9 (s), 160.0 (d), 164.0 (d, JCF ) 234 Hz). Anal. Calcd for
C15H10ClFN4: C, 59.91; H, 3.35; N, 18.63. Found: C, 59.76;
H, 3.43; N, 18.52.
1
3
conditions). H NMR (d6-DMSO, 200 MHz) δ 6.85 (dd, J ) 5
J. Org. Chem, Vol. 70, No. 13, 2005 5219

Stanetty et al.
Hz, 4J ) 1 Hz, 1H), 7.02 (d, 3J ) 8 Hz, 1H), 7.10 (d, 4J ) 1 Hz,
C18H19N5O: C, 67.27; H, 5.96; N, 21.79. Found: C, 67.56; H,
5.86; N, 21.66.
3
3
1H), 7.35 (t, J ) 8 Hz, 1H), 7.46 (d, J ) 5 Hz, 1H), 7.58 (d,
3
4
3J ) 5 Hz, 1H), 7.70 (d, J ) 8 Hz, 1H), 8.02 (t, J ) 1 Hz,
1H), 8.66 (d, 3J ) 5 Hz, 1H), 9.99 (s, 1H.); 13C NMR (d6-DMSO,
50 MHz) δ 102.5 (d), 109.4 (d), 117.2 (d), 117.9 (d), 118.1 (d),
121.0 (d), 130.1 (d), 133.0 (s), 136.2 (d), 141.9 (s), 148.2 (s),
159.8 (s), 161.4 (s), 162.6 (s). Anal. Calcd for C15H11ClN4O: C,
60.31; H, 3.71; N, 18.75. Found: C, 60.02; H, 3.84; N, 18.54.
3-[[4-[6-[(3-Chlorophenyl)amino]pyrimidin-4-yl]pyri-
din-2-yl]amino]-propanol, 12b. Prepared via general pro-
cedure 3. Mp 180-183 °C; 97% (0.43 g, 1.21 mmol, colorless
crystals); FCC PE/EtOAc 10:1; 1H NMR (d6-DMSO, 200 MHz)
3
3
δ 1.72 (quin, J ) 7 Hz, 2H), 3.35 (q, J ) 7 Hz, 2H), 3.50 (t,
3J ) 7 Hz, 2H), 4.55 (bs, 1H), 6.77 (t, J ) 7 Hz, 1H), 6.98 (d,
3
3J ) 5 Hz, 1H), 7.08 (d, J ) 8 Hz, 1H), 7.14 (s, 1H), 7.22 (s,
3
4-Chloro-6-(2-fluoropyridin-4-yl)pyrimidine, 9. Pre-
pared via general procedure 1. Mp 120-121 °C; 40% (1.56 g,
7.44 mmol, beige crystals); workup 2; FCC PE/EtOAc 20:1; 1H
NMR (d6-DMSO, 200 MHz) δ 7.88 (s, 1H), 8.08 (d, 3J ) 5 Hz,
1H), 8.41 (d, 3J ) 5 Hz, 1H), 8.47 (s, 1H), 9.16 (s, 1H); 13C
NMR (d6-DMSO, 50 MHz) δ 107.4 (d, 2JCF ) 40 Hz), 119.0 (d),
1H), 7.36 (t, 3J ) 8 Hz, 1H), 7.56 (d, J ) 8 Hz, 1H), 8.04 (bs,
3
3
1H), 8.10 (d, J ) 5 Hz, 1H), 8.79 (s, 1H), 9.94 (bs, 1H); 13C
NMR (d6-DMSO, 50 MHz) δ 32.4 (t), 38.1 (t), 58.7 (t), 103.4
(d), 105.1 (d), 108.2 (d), 117.9 (d), 119.0 (d), 121.9 (d), 130.3
(d), 133.2 (s), 141.3 (s), 144.6 (s), 148.5 (d), 158.3 (d), 159.8 (s),
160.1 (s), 160.8 (s). Anal. Calcd for C18H18ClN5O: C, 60.76; H,
5.10; N, 19.68. Found: C, 60.47; H, 4.94; N, 19.44.
3-[[4-[6-[(3-Trifluoromethylphenyl)amino]pyrimidin-
4-yl]pyridin-2-yl]amino]-propanol, 12c. Prepared via gen-
eral procedure 3. Mp 212-214 °C; 92% (0.36 g, 0.92 mmol,
yellow crystals); FCC PE/EtOAc 10:1; 1H NMR (d6-DMSO, 200
119.6 (d, 4JCF ) 4 Hz), 148.0 (d, 3JCF ) 8 Hz), 148.9 (d, 3JCF
15 Hz), 159.2 (d), 161.3 (d, JCF ) 4 Hz), 162.0 (s), 164.0 (d,
1JCF ) 234 Hz). Anal. Calcd for C9H5ClFN3: C, 51.57; H, 2.40;
N, 20.05. Found: C, 51.67; H, 2.67; N, 19.82.
)
4
4,6-bis-(2-Fluoropyridin-4-yl)pyrimidine, 10.18 Prepared
via general procedure 1. Mp 166-168 °C; 30% as byproduct
(1.50 g, 5.55 mmol, yellow crystals); FCC PE/EtOAc 20:1. Anal.
Calcd for C14H8F2N4: C, 62.22; H, 2.98; N, 20.73. Found: C,
61.92; H, 3.27; N, 20.85.
3
3
MHz) δ 1.72 (quin, J ) 7 Hz, 2H), 3.33 (q, J ) 7 Hz, 2H),
3
3
3.49 (t, J ) 7 Hz, 2H), 4.58 (bs, 1H), 6.75 (t, J ) 7 Hz, 1H),
6.98 (d, 3J ) 5 Hz, 1H), 7.14 (s, 1H), 7.24 (s, 1H), 7.35 (d, 3J )
8 Hz, 1H), 7.59 (t, 3J ) 8 Hz, 1H), 7.92 (d, 3J ) 8 Hz, 1H), 8.10
6-(2-Fluoropyridin-4-yl)-N-phenyl-4-pyrimidin-
amine, 11a. Prepared via general procedure 2. Mp 151-153
°C; 75% (0.45 g, 1.69 mmol, colorless crystals); FCC PE:EtOAc
3
(d, J ) 5 Hz, 1H), 8.26 (bs, 1H), 8.80 (s, 1H), 10.12 (bs, 1H);
13C NMR (d6-DMSO, 50 MHz) δ 32.4 (t), 38.2 (t), 58.8 (t), 103.5
(d), 105.2 (d), 108.2 (d), 115.5 (d), 118.5 (d), 123.1 (d), 124.3
(q, 1JCF ) 271 Hz), 129.7 (d, 2JCF ) 31 Hz), 130.0 (d), 140.7 (s),
144.6 (s), 148.6 (d), 158.3 (d), 159.9 (s), 160.3 (s), 160.9 (s).
Anal. Calcd for C19H18F3N5O: C, 58.61; H, 4.66; N, 17.99.
Found: C, 58.40; H, 4.57; N, 17.82.
1
3
5:1; H NMR (d6-DMSO, 200 MHz) δ 7.00 (d, J ) 8 Hz, 1H),
3
3
7.34 (s, 1H), 7.36 (t, J ) 8 Hz, 2H), 7.69 (bs, 1H), 7.71 (d, J
3
3
) 8 Hz, 2H), 7.89 (d, J ) 5 Hz, 1H), 8.40 (d, J ) 5 Hz, 1H),
8.75 (s, 1H), 9.88 (s, 1H); 13C NMR (d6-DMSO, 50 MHz) δ 103.7
2
4
(d), 106.4 (d, JCF ) 39 Hz), 119.0 (d, JCF ) 4 Hz), 120.1 (d),
3
122.9 (d), 128.8 (d), 139.3 (s), 148.5 (d, JCF ) 15 Hz), 150.3
N‘-[4-[6-(3-Chlorophenylamino)pyrimidin-4-yl]pyridin-
2-yl]-N,N-dimethylpropan-1,3-diamine, 12d. Compound
11b (0.43 g, 1.28 mmol) was refluxed for 4 h in 10 mL of N,N-
dimethyl-1,3-propandiamine. The reaction mixture was cooled
to room temperature and water was added. The product was
extracted with EtOAc, and the organic layer was washed with
brine, dried over Na2SO4, filtered, and evaporated. Recrystal-
lization from DIPE gave 12d. Yield 84% (0.41 g, 1.07 mmol,
yellow crystals); mp 185-187 °C; 1H NMR (d6-DMSO, 200
3
4
(d, JCF ) 8 Hz), 157.5 (d, JCF ) 4 Hz), 158.6 (d), 161.1 (s),
163.9 (d, 1JCF ) 234 Hz). Anal. Calcd for C15H11FN4: C, 67.66;
H, 4.16; N, 21.04. Found: C, 67.44; H, 3.94; N, 20.77.
N-(3-Chlorophenyl)-6-(2-fluoropyridin-4-yl)-4-pyrim-
idinamine hydrochloride, 11b. Prepared via general pro-
cedure 2. Mp 203-205 °C; 85% (1.10 g, 3.26 mmol, yellow
crystals); 1H NMR (d6-DMSO, 200 MHz) δ 7.16 (d, 3J ) 8 Hz,
3
1H), 7.40 (t, J ) 8 Hz, 1H), 7.36 (s, 1H), 7.70 (s, 1H), 7.80-
4
3
7.98 (m, 2H), 8.05 (t, J ) 1 Hz, 1H), 8.48 (d, J ) 5 Hz, 1H),
3
3
MHz) δ 1.69 (quin, J ) 7 Hz, 2H), 2.12 (s, 6H), 2.30 (t, J )
8.91 (s, 1H), offset (1H); 13C NMR (d6-DMSO, 50 MHz) δ 105.0
7 Hz, 2H), 3.30 (q, 3J ) 7 Hz, 2H), 6.79 (t, 3J ) 7 Hz, 1H), 6.98
2
4
(d), 107.0 (d, JCF ) 39 Hz), 118.8 (d), 119.3 (d, JCF ) 4 Hz),
119.8 (d), 123.1 (d), 130.4 (d), 133.1 (d), 140.3 (s), 147.9 (d,
3JCF ) 8 Hz), 148.8 (d, 3JCF ) 15 Hz), 154.8 (s), 156.9 (d), 161.1
(s), 163.8 (d, 1JCF ) 234 Hz). Anal. Calcd for C15H11Cl2FN4: C,
53.43; H, 3.29; N, 16.62. Found: C, 53.26; H, 3.35; N, 16.39.
3
3
(d, J ) 5 Hz, 1H), 7.08 (d, J ) 8 Hz, 1H), 7.12 (s, 1H), 7.20
3
3
(s, 1H), 7.37 (t, J ) 8 Hz, 1H), 7.56 (d, J ) 8 Hz, 1H), 8.04
3
(bs, 1H), 8.11 (d, J ) 5 Hz, 1H), 8.80 (s, 1H), 9.95 (bs, 1H);
13C NMR (d6-DMSO, 50 MHz) δ 27.0 (t), 39.2 (t), 45.2 (q), 57.0
(t), 103.3 (d), 105.0 (d), 108.0 (d), 117.9 (d), 118.9 (d), 121.9
(d), 130.3 (d), 133.1 (s), 141.3 (s), 144.4 (s), 148.6 (d), 158.2
(d), 159.7 (s), 160.1 (s), 160.8 (s). Anal. Calcd for C20H23ClN6:
C, 62.74; H, 6.05; N, 21.95. Found: C, 62.55; H, 5.95; N, 21.70.
N-(3-Trifluoromethylphenyl)-6-(2-fluoropyridin-4-yl)-
4-pyrimidinamine hydrochloride, 11c. Prepared via gen-
eral procedure 2. Mp 187-190 °C; 69% (0.66 g, 1.78 mmol,
1
3
yellow crystals); H NMR (d6-DMSO, 200 MHz) δ 7.43 (d, J
) 8 Hz, 1H), 7.59 (t, 3J ) 8 Hz, 1H), 7.60 (s, 1H), 7.70 (s, 1H),
7.88 (d, 3J ) 5 Hz, 1H), 8.01 (d, 3J ) 8 Hz, 1H), 8.28 (bs, 1H),
8.48 (d, 3J ) 5 Hz, 1H), 8.91 (s, 1H), offset (1H); 13C NMR (d6-
DMSO, 50 MHz) δ 105.0 (d), 106.9 (d, 2JCF ) 40 Hz), 116.3 (d,
4-[6-(Phenylamino)pyrimidin-4-yl]pyridin-2(1H)-
one, 13. Mp 284-286 °C; 15% (0.11 g, 0.42 mmol, pale yellow
crystals) as byproduct during the formation of 11a; FCC PE/
1
3
EtOAc 5:1; H NMR (d6-DMSO, 200 MHz) δ 6.71 (dd, J ) 5
Hz, 4J ) 1 Hz, 1H), 6.92 (d, 4J ) 1 Hz, 1H), 7.04 (t, 3J ) 8 Hz,
3JCF ) 4 Hz), 119.2 (d, JCF ) 4 Hz), 119.6 (d, JCF ) 4 Hz),
4
4
3
3
1H), 7.21 (s, 1H), 7.35 (t, J ) 8 Hz, 2H), 7.52 (d, J ) 5 Hz,
1
2
123.8 (d), 124.1 (q, JCF ) 270 Hz), 129.4 (d, JCF ) 31 Hz),
3
1H), 7.70 (d, J ) 8 Hz, 2H), 8.70 (s, 1H), 9.79 (s, 1H), offset
130.0 (d), 139.7 (s), 148.1 (d, 3JCF ) 8 Hz), 148.8 (d, 3JCF ) 15
(1H); 13C NMR (d6-DMSO, 50 MHz) δ 102.6 (d), 103.6 (d), 117.0
(d), 120.0 (d), 122.8 (d), 128.8 (d), 136.1 (d), 139.5 (s), 148.7
(s), 158.4 (d), 158.7 (s), 161.0 (s), 162.7 (s). Anal. Calcd for
C15H12N4O: C, 65.49; H, 4.84; N, 20.37. Found: C, 65.69; H,
4.76; N, 20.38.
4
1
Hz), 155.2 (d, JCF ) 4 Hz), 157.1 (d), 161.2 (s), 163.8 (d, JCF
) 234 Hz)
3-[[4-[6-(Phenylamino)pyrimidin-4-yl]pyridin-2-yl]ami-
no]-propanol, 12a. Prepared via general procedure 3. Mp
200-202 °C; 87% (0.47 g, 1.46 mmol, pale yellow crystals); FCC
EtOAc; 1H NMR (d6-DMSO, 200 MHz) δ 1.71 (quin, 3J ) 7
Hz, 2H), 3.32 (q, 3J ) 7 Hz, 2H), 3.50 (q, 3J ) 7 Hz, 2H), 4.55
(t, 3J ) 7 Hz, 1H), 6.74 (t, 1H, 3J ) 7 Hz), 6.97 (dd, 3J ) 5 Hz,
Acknowledgment. The authors thank Syngenta
Crop Protection, Basel for financial support.
3
4J ) 1 Hz, 1H), 7.05 (t, J ) 8 Hz, 1H), 7.12 (s, 1H), 7.20 (s,
3
3
1H), 7.35 (t, J ) 8 Hz, 2H), 7.71 (d, J ) 8 Hz, 2H), 8.09 (d,
3J ) 5 Hz, 1H), 8.71 (s, 1H), 9.77 (s, 1H); 13C NMR (d6-DMSO,
50 MHz) δ 32.4 (t), 38.1 (t), 58.7 (t), 102.7 (d), 105.1 (d), 108.2
(d), 120.0 (d), 122.7 (d), 128.9 (d), 139.7 (s), 144.8 (s), 148.5
(d), 158.4 (d), 159.8 (s), 159.9 (s), 161.1 (s). Anal. Calcd for
Supporting Information Available: Crystallographic
data for compound 6c. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0505223
5220 J. Org. Chem., Vol. 70, No. 13, 2005