A new and productive route to 1-heteroarylcyclopropanols

Article abstract of DOI:10.1002/ejoc.200390093

(E/Z)-2-(1-Allyloxycyclopropyl)-3-methoxyacrylonitrile (4All) was designed and prepared in five steps (58% overall yield) from ethyl cyclopropylidenacetate as a valuable precursor to various 1-heteroarylcyclopropanols. Its condensation with amidines, guan

Full text of DOI:10.1002/ejoc.200390093

FULL PAPER
A New and Productive Route to 1-Heteroarylcyclopropanols[‡]
Vladimir N. Belov,[a,b] Andrei I. Savchenko,[a] Viktor V. Sokolov,[a] Alexander Straub,[c][‡‡] and
Armin de Meijere*[a,b]
Dedicated to Professor Henry Shine on the occasion of his 80th birthday
Keywords: Cyclopropanols / Metabolism / Nitrogen heterocycles / Protecting groups / Small ring systems
(E/Z)-2-(1-Allyloxycyclopropyl)-3-methoxyacrylonitrile
(4-
soluble guanylate cyclase. Direct cleavage of the allyl ether
protecting group [by palladium-catalyzed substitution with
lithium p-toluenesulfinate in AcOH or treatment with c-
HexMgBr/Ti(OiPr)4] gives highly functionalized, sterically
congested 1-heteroarylcyclopropanols 29, 30, and 34 with in-
tact amino and ester groups.
All) was designed and prepared in five steps (58% overall
yield) from ethyl cyclopropylidenacetate as a valuable pre-
cursor to various 1-heteroarylcyclopropanols. Its condensa-
tion with amidines, guanidine, hydrazine, and methyl thio-
glycolate and subsequent removal of the allyl protecting
group yields 1-heteroarylcyclopropanols such as 1-OH (36%
over 2 steps), a very potent NO-independent stimulator of
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
to its main metabolite 1-OH, which displayed strong hypo-
tensive activity in vivo (rats and dogs). Its first synthesis
was achieved,[3] albeit in a poor yield of less than 1%, by
reductive cyclopropanation of the ester 2 with the Kagan
reagent (Sm/CH2I2), by application of Imamoto’s proced-
ure.[4]
The recent discovery that a particular 1-heteroarylcyclo-
propanol (1-OH) is a potent new NO-independent stimul-
ator of the soluble guanylate cyclase (sGC) has triggered an
interest in the development of a viable synthesis of
this compound and of functionally substituted 1-
heteroarylcyclopropanols in general, because of their poten-
tial physiological activities.[1] Compound 1-OH was first
isolated from rat hepatocyte suspensions after administra-
tion of the cyclopropyl-substituted 4-aminopyrimidine de-
rivative 1-H (BAY 41-2272), which had been developed as
a most promising stimulator of sGC.[2] It was found that
the long-lasting oral activity of BAY-2272 is partially due
[‡]
Cyclopropyl Building Blocks in Organic Synthesis, 84. Part 83:
A. de Meijere, Andrei Leonov, Thomas Heiner, Mathias
Noltemeyer, M. Teresa Bes, Eur. J. Org. Chem., 2003, in press.
Part 82: T. Voigt, H. Winsel, A. de Meijere, Synlett 2002,
1362Ϫ1364.
Scheme 1. Isolation of 1-hetarylcyclopropanol 1-OH, a main meta-
bolite of BAY 41-2272 in rats and dogs;[1] reagents and condi-
tions:[3] a) rat hepatocytes (in vivo); b) Sm/CH2I2, THF, 50 °C,
70 min; 1  HCl; RP18 chromatography, 1%
[a]
Institut für Organische Chemie, Georg-August-Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551/399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b]
In order to enable extensive biological tests to be con-
ducted, it was essential to make this compound 1-OH avail-
able in larger quantities by a productive total synthesis.
KAdemCustomChem GmbH,
Brombeerweg 13, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551/23423
[c]
Institute of Medicinal Chemistry, Pharma Research Center,
BAYER AG,
42096 Wuppertal, Germany
Results and Discussion
[‡‡]
Current address: BAYER Cropscience, Bldg. 6550,
40789 Monheim, Germany
A survey of the literature found only three reports con-
cerning the formation of 1-heteroarylcyclopropanols.[5] 2-
Fax: (internat.) ϩ 49-(0)2173/384880
E-mail: alexander.straub.as@bayer-ag.de
Eur. J. Org. Chem. 2003, 551Ϫ561  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0551 $ 20.00ϩ.50/0
551

V. N. Belov, A. I. Savchenko, V. V. Sokolov, A. Straub, A. de Meijere
FULL PAPER
Alkanoylpyridines and -pyrazines, 4-alkanoylpyrimidines,
and 3-isopentanoylpyridazine undergo isomerization of
their ArCOCH2CH2R fragments upon irradiation, to give
1-arylcyclopropanol fragments through diradical interme-
diates. However, this did not appear to be a viable process
for the preparation of reasonable quantities of pure 1-het-
eroarylcyclopropanols such as 1-OH, especially since it is
limited to 2-alkanoyl-substituted N-heterocycles. The Kul-
inkovich reaction, which constitutes an excellent route to 1-
alkylcyclopropanols from aliphatic carboxylates,[6,7] failed
to yield 1-OH from the corresponding ethyl carboxylate 2.
Another obvious synthetic strategy, designed on the basis
of the known reactions between 3-methoxyacrylonitriles
and 1,3-dinucleophiles,[8] requires the heteroamidine 3[2,3]
and an appropriately protected 2-(1-hydroxycyclopropyl)-3-
methoxyacrylonitrile 4-R as key intermediates. These
should yield, through a condensation reaction, the pro-
tected cyclopropanol 1-OR, and its subsequent deprotec-
tion should provide 1-OH (Scheme 2).
Scheme 3. Attempted synthesis of 4-THP from methyl 3-bromopro-
pionate: a) EtMgBr (2.2 equiv.), Ti(OiPr)4 (0.1 equiv.), Et2O/THF,
20 °C, 4 h; b) 3,4-dihydro-2H-pyran, py·TsOH, CH2Cl2, 0 Ǟ 20
°C, 16 h; c) NaN3, DMF, 75 °C, 4 h; d) diphenylacetylene, 10%
Pd/C, p-xylene, reflux, 6 h; e) KH, HCO2Me, THF, 0 Ǟ 20 °C;
(MeO)2SO2, 18-crown-6, 20 Ǟ 50 °C
Scheme 2. Synthetic strategy for the construction of 1-hetarylcyclo-
propanol 1-OH
Since cyclopropanols are reasonably stable towards
acid,[9] the first choice of protecting group was the tetrahy-
dropyranyl (THP) moiety. It was therefore attempted to
prepare the building block 4-THP from methyl 3-bromo-
propanoate (5, Scheme 3). Conversion of 5 into the cyclo-
propanol 6 was achieved in high yield by use of the
EtMgBr/Ti(OiPr)4 reagent.[10] After protection of 6 with di-
hydropyran under standard conditions,[9d] the resulting sub-
Scheme 4. Synthesis of the main building blocks 4-R: a) ROH,
NaH, 20 °C, 4 h; b) SOCl2, CH2Cl2, reflux, 2 h; concd. aq. NH3
(13a); c) N,NЈ-carbonyldiimidazole, THF, 25 °C, 2.5 h; NH4OAc,
20 °C, 16 h (13b); d) TFAA/py, CH2Cl2, 0 Ǟ 20 °C, 16 h; e) KH,
HCO2Me, THF, 0 Ǟ 20 °C, 3 h; f) (MeO)2SO2, 18-crown-6, 0 Ǟ
50 °C; g) NaH, THF, room temp., 2 h, then (MeO)2SO2, 40 °C, 2 h
stituted THP ether 7 was transformed into the azidoethyl addition of 4-methoxybenzyl alcohol or allyl alcohol to
derivative 8 in very high yield. By adoption of the known ethyl cyclopropylideneacetate (11)[12] and hydrolysis of the
procedure[11] with some modifications, the latter could be ester group afforded the (1-alkoxycyclopropyl)acetic acids
converted into the nitrile 9, albeit under drastic conditions 12a and 12b. Their conversion into the amides 13a and 13b
and only in moderate yield. Separation of 9 from a small was accomplished by activation with N,NЈ-carbonyldiimid-
amount of the triazole by-product 10 was achieved by col- azole, followed by treatment with NH4OAc. Conventional
umn chromatography. However, all attempts to transform transformation of 12a into the acyl chloride (SOCl2) and
the nitrile 9 into the desired methoxymethylene derivative subsequent treatment with NH3 was found to give a signi-
4-THP failed, probably due to the large steric demand of ficantly lower yield of 13a when this reaction was carried
the THP group. This approach is still important, as it may out on a larger scale. Dehydration of the amides 13a and
be used for the synthesis of other (1-alkoxycyclopropyl)ace- 13b to provide the nitriles 14a and 14b proceeded quantitat-
tonitriles 14a and 14b (Scheme 4) with sterically less de- ively under conditions described by Della et al.[13] The sub-
manding ether protecting groups, such as methoxymethyl, sequent two-step sequence Ϫ condensation with methyl
methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl- formate and KH, followed by methylation with dimethyl
oxymethyl, introduced by treatment of the corresponding sulfate Ϫ also worked well and afforded the desired building
chlorides with the cyclopropanol 6.
blocks 4-R. A one-pot operation without isolation of the
An alternative route to (1-alkoxycyclopropyl)acetonitriles enol 15b was found to be superior, especially when the
14a and 14b Ϫ with 4-methoxybenzyl and allyl protecting methylation was performed in the presence of 18-crown-6.
groups, respectively Ϫ was developed (Scheme 4). Michael O-Methylation of the enols 15 enhances the reactivity of
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Eur. J. Org. Chem. 2003, 551Ϫ561

A New and Productive Route to 1-Heteroarylcyclopropanols
FULL PAPER
the α,β-unsaturated nitrile fragment towards nucleophiles.
Eventually, the desired isomerization of 16b to the pro-
While the attempted direct condensation of the enol 15a penyl ether (Z)-17 was achieved by a classical method, by
with the amidine 3 failed to yield any product, heating of treatment with potassium tert-butoxide in DMSO at 85Ϫ95
4-PMB or 4-All with 3 and sodium ethoxide in ketone-free °C (Scheme 7). In accordance with Warren et al.,[15] 2 equiv.
ethanol furnished the desired (1-alkoxycyclopropyl)pyrimi- of tBuOK per equivalent of the starting compound were
dines 16a and 16b in good yields (Scheme 5). To go to com- necessary to bind the ‘‘active’’ H. The propenyl ether (Z)-
pletion, these reactions required 1.4Ϫ1.8 equiv. of the amid- 17 was isolated by chromatography on neutral Al2O3. Final
ine 3 and 36 h heating under reflux.
deprotection was effected by gentle heating of 17 in dilute
methanolic HCl, and so the desired metabolite 1-OH was
obtained in an overall yield of 34% over both steps. After
considerable optimization, an even better yield (69%) was
achieved by direct cleavage of the allyl ether 16b with the
RMgBr/Ti(OiPr)4 reagent recently recommended by Cha et
al. for the cleavage of allyl ethers under mild conditions.[16]
The ethyl-substituted by-product 20 was formed when
ethylmagnesium bromide was used in this deprotection.
However, this alkylation did not occur with cyclohexylmag-
nesium bromide.
Scheme 5. Synthesis of the O-protected precursors 16a and 16b of
the metabolite 1-OH: a) EtOH, EtONa, reflux, 20 h; b) Ph3CBF4
(2 equiv.), CH2Cl2, room temp., 16 h; reflux, 5 h
Scheme 7. Synthesis of the metabolite 1-OH by deprotection of the
allyl ether 16b: a) tBuOK (2 equiv.), DMSO, 85Ϫ95 °C, 1.5 h; b)
0.5  aq. HCl, MeOH, 55Ϫ60 °C, 1.5 h; c) THF/diethyl ether,
cHexMgBr (1 equiv.), Ti(OiPr)4 (1 equiv.), then cHexMgBr (4
equiv.), 10 Ǟ 20 °C, 3 h; d) PdCl2 (1 equiv.), AcONa, AcOH, p-
MeC6H4SO2Li (2.6 equiv.), Pd(Ph3P)4 (13 mol %), 50 °C, 90 min
All attempts to deprotect the p-methoxybenzyl ether 16a
and to obtain the metabolite 1-OH failed. Oxidative depro-
tection either left the starting compound intact (DDQ,
CH2Cl2/H2O), or, when Ph3CBF4 was used as a reagent,
destroyed the pyrimidine ring and yielded N-triphenylme-
thylated amidine 3-Tr (Scheme 5). Attempted hydro-
genolysis at ambient pressure in the presence of 34% Pd/C
(10% Pd) in MeOH/THF left the starting compound 16a
intact. Isomerization of the allyl ether group in 16b into the
propenyl ether turned out to be difficult. Treatment with
the Wilkinson catalyst (Ph3P)3RhCl failed to give any prod-
uct. The deprotection method of Scheffold et al. (Pd/C,
EtOH, 1  aq. HCl, reflux)[14] resulted in opening of the
cyclopropane ring, and gave 1-arylpropanone 18 and 1-
aryl-3-ethoxypropanone 19 (Scheme 6). The experiment
thus gave indirect evidence that the cyclopropanol 1-OH
had been formed.
The highest yield of the metabolite 1-OH was obtained
when the allyloxy group was removed in the presence of
100 mol % of PdCl2 with sodium acetate and 13 mol % of
Pd(Ph3P)4 in glacial acetic acid with lithium p-toluenesulf-
inate (as a scavenger for the allyl group) at 50 °C. The reac-
tion was complete within 1.5 h, and no cyclopropyl ring-
opening product was found. This combination of two
known procedures was found to be efficient, while neither
PdCl2/AcONa in AcOH,[17] nor Pd(Ph3P)4 in AcOH
with[18] or without[19] a stoichiometric amount of p-tolu-
enesulfinic acid removed the allyl group in 16b at 50 °C,
and higher temperatures were found to cause opening of
the cyclopropanol ring. The obvious disadvantage of this
method Ϫ the high consumption of palladium Ϫ may be
tolerated if the molecular weight of the starting allyl ether
is high or the reaction is run on a small scale. However, an
advantage is that acetic acid is used as a solvent. Unlike
tetrahydrofuran or diethyl ether as used in Cha’s proced-
ure,[16] acetic acid easily dissolves most nitrogen hetero-
cycles and thus facilitates the deprotection reaction.
Appropriate conditions for effective cleavage of the al-
lyloxy group in the protected cyclopropanol 16b having
been found, further heterocyclization reactions of 3-me-
thoxyacrylonitrile 4-All aimed at the preparation of other
Scheme 6. Opening of the cyclopropanol ring during deprotection
of the allyl ether 16b: a) 10% Pd/C, EtOH, 1  aq. HCl, reflux, 40 h 1-heteroarylcyclopropanols were studied. Well-known con-
Eur. J. Org. Chem. 2003, 551Ϫ561
553

V. N. Belov, A. I. Savchenko, V. V. Sokolov, A. Straub, A. de Meijere
FULL PAPER
densations of 2-substituted 3-hydroxy-, 3-alkoxy-, or 3-tosy-
loxyacrylonitriles with 1,2-dinucleophiles (hydrazine,[20] hy-
droxylamine,[21] and methyl thioglycolate[22]) and 1,3-dinu-
cleophiles (guanidine[8aϪ8c,8eϪ8h] and thiourea[8d]) afforded
various five- and six-membered heterocycles, though in
variable yields. In the case of 4-All, treatment with a large
excess of anhydrous hydrazine gave 3-aminopyrazole 21 in
57% yield (Scheme 8). Heating of 4-All in the presence of 1
equiv. of hydroxylamine hydrochloride with sodium me-
thoxide in methanol did not produce the expected isoxazole.
Condensation of 4-All with methyl thioglycolate gave the
desired thiophene 22 as the main product, together with
methyl 4-cyano-3-ethylthiophene-2-carboxylate (23). The
formation of the two products 22 and 23 may be explained
by assuming that the reaction proceeds via the intermediate
24. A similar intermediate was isolated on treatment of
methyl thioglycolate with 2-benzyl-3-tosyloxyacrylonitri-
le.[22f] The direct cyclization of this intermediate 24 yields
aminothiophene 22 as the main product, while the allyloxy
group may isomerize to some extent under the influence of
sodium methoxide during the prolonged heating in meth-
anol, giving the propenyl ether. Methanolysis of the latter
should yield cyclopropanol 25, which, under the basic con-
ditions, undergoes ring-opening to the ketone 26. An intra-
molecular aldol condensation of this ketone then provides
the cyanothiophenecarboxylate 23 (Scheme 8).
Scheme 9. Deprotection of hetarylcyclopropyl allyl ethers: a) PdCl2
(0.6Ϫ0.8 equiv.), AcONa, AcOH, pMeC6H4SO2Li (1.1Ϫ1.5 equiv.),
Pd(Ph3P)4 (7 mol %), 40 °C, 30Ϫ90 min; b) Ti(OiPr)4 (2 equiv.),
cHexMgBr (6 equiv.), Et2O, 20 °C, 16 h; c) tBuOK (4 equiv.),
DMSO, 85Ϫ95 °C, 1.5 h
(Scheme 9). Under the same conditions [PdII/Pd0, pMeC6H4-
SO2Li in AcOH at 40 °C), however, none of the expected
cyclopropanol was isolated from the thiophene derivative
22, the two ketones 31 and 32 being obtained instead
(Scheme 9). The cyclopropanol 30 or its palladium cyclo-
propoxide precursor appear to be particularly prone to
ring-opening by attack of acetic acid to yield the ketone
31. The palladium-mediated ring-opening of 1-alkyl- and 1-
alkenylcyclopropanols was recently reported by Cha to
yield the corresponding α,β-unsaturated ketones.[23] Appar-
ently, Michael addition of the p-toluenesulfinate anion, pre-
sent in the mixture as a scavenger for the allyl group, across
the double bond of the intermediately formed α,β-unsatur-
ated ketone may easily explain the formation of the β-aryl-
sulfonyl-substituted ketone 32. An analogous reaction
mode was observed when the allyl ether 16b was heated in
ethanol in the presence of palladium on charcoal and dilute
aq. HCl (Scheme 6).
Eventually, the deprotection of the thiophene derivative
22 was successfully accomplished without rearrangement by
gradual addition of an excess of cyclohexylmagnesium
bromide in the presence of 2 equiv. of titanium tetraisoprop-
oxide at ambient temperature in diethyl ether. The methyl
ester group remained intact, even though it was exposed
overnight to a sixfold excess of the Grignard reagent. The
moderate yield of 30 (46%) may be due to losses of the
highly polar product during the workup and chromato-
graphy. Probably, this new procedure, modified with respect
to that of Cha et al.,[16] should also be usable to cleave any
other allyl 1-arylcyclopropyl ethers containing one or more
methyl ester group(s) attached to the heterocyclic fragment.
However, the allyl 1-hetarylcyclopropyl ethers must be suf-
ficiently soluble in diethyl ether or tetrahydrofuran. Other-
wise (e.g., for the 2,4-diaminopyrimidine derivative 27), the
deprotection with cyclohexylmagnesium bromide and tita-
nium tetraisopropoxide does not work.
Scheme 8. Condensation reactions of 4-All, affording various O-
allyl ethers of 1-heteroarylcyclopropanols: a) NH2NH2, MeOH, re-
flux, 16 h; b) HSCH2CO2Me, MeONa, MeOH, reflux, 16 h; c)
guanidine·HCl, MeONa, MeOH, reflux, 24 h; d) thiourea,
MeONa, MeOH, reflux, 24 h
Treatment of 4-All with guanidine gave the 2,4-diamino-
pyrimidine 27 in a very high yield, while under similar condi-
tions thiourea produced only 30% of 4-amino-2-mercapto-
pyrimidine 28.
Thanks to the experience obtained during the deprotec-
tion of the allyl ether 16b, cleavage of the allyloxy group
An attempt to isomerize the allyloxy group in 27 to the
in the 3-aminopyrazole derivative 21 was easily achieved, propenyl ether by treatment with potassium tert-butoxide
yielding 71% of the corresponding cyclopropanol 29 in DMSO at 85Ϫ95 °C was accompanied by decomposition
554
Eur. J. Org. Chem. 2003, 551Ϫ561

A New and Productive Route to 1-Heteroarylcyclopropanols
FULL PAPER
(m, 1 H), 0.95Ϫ1.14 (m, 1 H), 1.39Ϫ1.82 (m, 6 H), 1.82Ϫ1.98 (m,
1 H), 2.30Ϫ2.52 (m, 1 H), 3.43Ϫ3.72 (m, 3 H), 3.78Ϫ3.97 (m, 1
H), 4.64Ϫ4.78 (m, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 11.1 (CH2),
12.5 (CH2), 20.2 (CH2), 25.2 (CH2), 29.8 (CH2), 31.7 (CH2), 40.2
(CH2), 61.1 (C), 63.5 (CH2), 99.1 (CH) ppm.
of the starting material, and only afforded a small isolated
amount of 2,4-diamino-5-(1-methylthiocyclopropyl)pyrimi-
dine (33), the mode of formation of which is unknown.
Eventually, palladium-mediated deprotection of 27 gave the
required 1-(2,4-diaminopyrimidin-5-yl)cyclopropanol (34)
in acceptable yield (54%).
All attempts to deprotect the 1-(4-amino-2-mercaptopyri-
midin-5-yl)cyclopropyl ether 28 by any of these procedures
failed. The solubility of 28 in tetrahydrofuran is very low,
and so the modified procedure similar to that of Cha[16]
cannot be used.
2-{[1-(2-Azidoethyl)cyclopropyl]oxy}tetrahydro-2H-pyran (8): This
compound was synthesized from 7 (7.00 g) in 92% yield (5.35 g) by
a known procedure.[11] B.p. 105Ϫ108 °C (0.01 Torr, Kugelrohr). 1H
NMR (CDCl3): δ ϭ 0.40Ϫ0.52 (m, 2 H), 0.73Ϫ0.85 (m, 1 H),
0.95Ϫ1.06 (m, 1 H), 1.40Ϫ1.67 (m, 6 H), 1.70Ϫ1.82 (m, 1 H),
2.05Ϫ2.17 (m, 1 H), 3.39Ϫ3.59 (m, 3 H), 3.83Ϫ3.91 (m, 1 H),
4.68Ϫ4.71 (m, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 11.2 (CH2), 12.5
(CH2), 20.5 (CH2), 25.2 (CH2), 31.8 (CH2), 35.7 (CH2), 48.2 (CH2),
59.6 (C), 63.5 (CH2), 99.2 (CH) ppm. IR (neat): ν˜ ϭ 3088 cmϪ1,
2097. C10H17N3O2 (211.26): calcd. C 56.85, H 8.11, N 19.89; found
C 57.11, H 8.29, N 19.76.
Conclusion
Protection of alcohols as allyl ethers is quite common,
and many new methods for their cleavage have been de-
veloped during the last two decades.[24] Most reported ap-
plications have been concerned with carbohydrates. This in-
vestigation has shown that 1-heteroarylcyclopropanols can
most favorably be prepared through the allyl-protected in-
termediates. Two efficient cleavage procedures have been
elaborated for a variety of allyl 1-hetarylcyclopropyl ethers
prepared from (E/Z)-2-(1-allyloxycyclopropyl)-3-methoxy-
acrylonitrile (4-All).
[1-(Tetrahydropyran-2-yloxy)cyclopropyl]acetonitrile (9) and 4,5-Di-
phenyl-1-(2-{1-[(tetrahydropyran-2-yl)oxy]cyclopropyl}ethyl)-
1H-1,2,3-triazole (10): Pd/C (600 mg, 10% Pd in the oxidized form,
Merck) in p-xylene (20 mL) was stirred under H2 at ambient pres-
sure for 1 h, and the suspension was then heated under reflux under
N2 for 1 h, in order to remove hydrogen adsorbed on the catalyst.
A solution of the azide 8 (3.17 g, 15.0 mmol) and diphenylacetylene
(3.20 g, 18.0 mmol) in p-xylene (4 mL) was then added dropwise to
this suspension over 15 min. The mixture was heated under reflux
for 6 h and then filtered through Celite. After the solvent had
been removed in vacuo, the oily residue (6.10 g) was purified by
chromatography on silica gel (75 g). Elution with PE removed stil-
bene, and gradient elution with PE/EtOAc (10:1 Ǟ 5:1) afforded
1.35 g of the crude title compound, which was distilled (b.p.
100Ϫ110 °C at 0.01 Torr in a Kugelrohr) to give pure 9 (1.32 g,
Experimental Section
General Remarks: Melting points (uncorrected) were determined in
capillaries with a Büchi 510 apparatus. NMR spectra were recorded
with a Bruker AM 250 instrument at 250 (1H) and 62.9 MHz (13C
and DEPT). All spectra were calibrated against tetramethylsilane
as an internal standard (δ ϭ 0) or the signals of the residual pro-
tons of deuterated solvents: δ ϭ 7.26 for CHCl3, δ ϭ 2.50 for
[D5]DMSO, and δ ϭ 3.30 for [D3]MeOH. Multiplicities of signals
are described as follows: s ϭ singlet, d ϭ doublet, t ϭ triplet, q ϭ
quadruplet, quint ϭ quintuplet, mc ϭ centrosymmetrical multiplet.
Coupling constants (J) are given in Hz; J values in 13C NMR spec-
tra refer to 13C-19F couplings. EI-MS data were recorded with Fin-
nigan MAT 95 and Varian CH 5 spectrometers (70 eV). HRMS
data were acquired with a Micromass LCT (TOF MS, electrospray
ionization, positive and negative modes). IR: Bruker IFS 66 (FT-
IR) spectrophotometer, measured as KBr pellets or oils between
KBr plates. Analytical TLC was performed on MachereyϪNagel
ready-to-use plates (AluGram Sil G/UV254). Detection was under a
UV lamp at 254 nm, development with molybdatophosphoric acid
solution (5% in EtOH) or 0.5% aq. KMnO4. Column chromato-
graphy: Merck silica gel, grade 60, 230Ϫ400 mesh; neutral alumi-
num oxide (ICN), activity grade III. Elemental analyses were car-
ried out at the Mikroanalytisches Laboratorium des Instituts für
Organische Chemie der Georg-August-Universität Göttingen.
Solvents were purified by standard procedures. Organic solutions
were dried with MgSO4, unless otherwise stated. PE ϭ petroleum
ether.
1
49%). H NMR (CDCl3): δ ϭ 0.67Ϫ0.77 (m, 2 H), 0.86Ϫ0.92 (m,
1 H), 1.08Ϫ1.13 (m, 1 H), 1.44Ϫ1.80 (m, 6 H), 2.56 (d, J ϭ
17.1 Hz, 1 H), 3.12 (d, J ϭ 17.1 Hz, 1 H), 3.50Ϫ3.60 (m, 1 H),
3.90Ϫ4.05 (m, 1 H), 4.77Ϫ4.82 (m, 1 H) ppm. 13C NMR (CDCl3):
δ ϭ 11.6 (CH2), 13.2 (CH2), 19.5 (CH2), 25.1 (CH2), 26.0 (CH2),
31.2 (CH2), 58.1 (C), 62.9 (CH2), 99.5 (CH), 117.9 (C) ppm. IR
(neat): ν˜ ϭ 3089 cmϪ1, 2247. C10H15NO2 (181.24): calcd. C 66.27,
H 8.34; found C 66.10, H 8.45. Elution with EtOAc gave 10 (0.41 g,
7%), which was recrystallized from PE to yield a colorless solid,
m.p. 78Ϫ79 °C. 1H NMR (CDCl3): δ ϭ 0.25Ϫ0.35 (m, 2 H),
0.66Ϫ0.76 (m, 1 H), 0.85Ϫ0.95 (m, 1 H), 1.20Ϫ1.30 (m, 1 H),
1.34Ϫ1.95 (m, 5 H), 1.95Ϫ2.10 (m, 1 H), 2.15Ϫ2.30 (m, 1 H),
3.30Ϫ3.40 (m, 1 H), 3.58Ϫ3.68 (m, 1 H), 4.40Ϫ4.55 (m, 2 H),
4.58Ϫ4.62 (m, 1 H), 7.15Ϫ7.30 (m, 3 H), 7.35Ϫ7.40 (m, 2 H),
7.45Ϫ7.60 (m, 5 H) ppm. 13C NMR (CDCl3): δ ϭ 10.9 (CH2), 12.2
(CH2), 19.9 (CH2), 25.1 (CH2), 31.5 (CH2), 36.8 (CH2), 45.6 (CH2),
59.2 (C), 63.1 (CH2), 98.6 (CH), 126.7 (CH), 127.5 (CH), 128.0
(C), 128.3 (CH), 129.1 (CH), 129.5 (CH), 130.1 (CH), 131.0 (C),
133.9 (C), 144.1 (C) ppm. IR (KBr): ν˜ ϭ 3067, 3000, 2957, 2936,
1457, 1444, 1354, 1210, 1201, 1130, 1119, 1107, 1050, 1030, 998.
MS (CI): m/z (%) ϭ 390 (100) [M ϩ Hϩ], 368 (12), 284 (14), 102
(18). C24H27N3O2 (389.50): calcd. C 74.01, H 6.99; found C 74.26,
H 7.11.
2-[1-(4-Methoxybenzyloxy)cyclopropyl]acetic Acid (12a): NaH
(450 mg of a 60% suspd. in mineral oil, 11.2 mmol) was washed
three times with anhydrous pentane and dried in vacuo, and p-
methoxybenzyl alcohol (19.0 mL, 21.1 g, 0.152 mol) was added
dropwise with stirring. After the sodium hydride had dissolved,
2-{[1-(2-Bromoethyl)cyclopropyl]oxy}tetrahydro-2H-pyran (7): Ester
5 (5.01 g, 30.0 mmol) was converted according to the published
procedure[10] into cyclopropanol 6 (4.54 g, 92%), which was pro-
tected with dihydro-2H-pyran in CH2Cl2 as described[9d] to give ethyl cyclopropylideneacetate (11,[12] 6.32 g, 50.1 mmol) was added
the title compound (7.00 g, 92%) with b.p. 75Ϫ85 °C (0.01 Torr,
dropwise with stirring and cooling with ice/water over 5 min. The
reaction mixture was stirred at ambient temp. for 4 h and diluted
Kugelrohr). 1H NMR (CDCl3): δ ϭ 0.38Ϫ0.62 (m, 2 H), 0.68Ϫ0.86
Eur. J. Org. Chem. 2003, 551Ϫ561
555

V. N. Belov, A. I. Savchenko, V. V. Sokolov, A. Straub, A. de Meijere
FULL PAPER
with EtOH (50 mL), and a solution of NaOH (4.0 g, 0.10 mol) in
H2O (20 mL) was added. After the mixture had been stirred for an
was kept overnight at ϩ4 °C. The product was removed by filtra-
tion, washed with pentane/diethyl ether (2:1, 5 mL) and dried in
additional 4 h at room temp., EtOH was evaporated in vacuo, and air to give a colorless solid (904 mg, 80%) with m.p. 135Ϫ137 °C
the residue was mixed with H2O (50 mL) and extracted with diethyl
ether (3 ϫ 30 mL). The aqueous layer was carefully acidified with
1  aq. HCl, and extracted with diethyl ether (3 ϫ 30 mL). The
combined organic solutions were washed with water (20 mL),
dried, and concentrated in vacuo to yield the title compound as a
yellowish oil, which soon crystallized to a solid with m.p. 71Ϫ74
°C. Yield 10.7 g (90%) of 12a, which was used in the next step
without further purification. 1H NMR (CDCl3): δ ϭ 0.69 (mc, 2
(dec.). 1H NMR (CDCl3/[D6]DMSO, 10:1; signals of the major iso-
mer are marked with *): δ ϭ 0.60Ϫ0.91 (m, 4 H), 3.60 (s, 3 H),
4.21*/4.27 (s, 2 H), 6.66 (d, J ϭ 8.4 Hz, 2 H), 7.01Ϫ7.05 (m, 2 H),
7.13/7.14* (s, 1 H), 10.62 (br. s, 1 H) ppm. 13C NMR (CDCl3/
[D6]DMSO, 10:1; signals of the major isomer are marked with *):
δ ϭ 12.7*/13.6 (CH2), 54.7 (OMe), 56.0/58.7* (CϪO), 68.1*/68.9
(CH2O), 88.0*/89.2 (CN), 113.0/113.1* (CH), 116.7*/119.8 (C),
128.7*/128.9 (CH), 129.4*/129.7 (C), 158.5 (C), 159.2/160.2* (CH)
H), 1.01 (mc, 2 H), 2.68 (s, 2 H), 3.78 (s, 3 H), 4.50 (s, 2 H), 6.85 ppm. IR (KBr): ν˜ ϭ 3424, 3091, 3039, 2979, 2211, 1657, 1612,
(m, 2 H), 7.23 (m, 2 H), 10.6 (br. s, 1 H) ppm. 13C NMR (CDCl3): 1516, 1249, 1207, 1183, 1081, 1027. MS (EI): m/z (%) ϭ 245 (1)
δ ϭ 12.5 (CH2), 39.4 (CH2), 55.1 (MeO), 58.8 (CϪO), 69.1 [Mϩ], 121 (100) [C8H9Oϩ]. HRMS: calcd. for C14H14NO3 [Mϩ
Ϫ
(CH2O), 113.2 (CH), 129.8 (C and CH), 159.0 (C), 176.8 (C) ppm.
MS (EI): m/z (%) ϭ 236 (0.4) [Mϩ], 210 (0.4) [Mϩ Ϫ C2H2], 121
(100) [C8H9Oϩ].
H] 244.0974; found 244.0993.
(E/Z)-3-Methoxy-2-[1-(4-methoxybenzyloxy)cyclopropyl]acrylo-
nitrile (4-PMB). Method A: Compound 15a (100 mg, 0.408 mmol)
in diethyl ether (2 mL) was methylated by addition of an excess of
diazomethane in diethyl ether at 0 °C. When the spot correspond-
ing to 15a was no longer detectable on the TLC plate (Rf ഠ 0.1,
CH2Cl2), the solvent was evaporated, and the product was separ-
ated from an impurity with Rf ϭ 0 by filtering through SiO2 (1 g)
and eluting with CH2Cl2. Yield 70 mg (66%) of 4-PMB as a color-
less oil. Method B: NaH (248 mg of a 60% susp. in mineral oil,
6.20 mmol) was added in small portions to 15a (763 mg,
3.11 mmol) in THF (5 mL). The mixture was stirred at ambient
2-[1-(4-Methoxybenzyloxy)cyclopropyl]acetamide (13a): A solution
of the acid 12a (2.50 g, 10.6 mmol) and SOCl2 (2 mL) in CH2Cl2
(30 mL) was heated under reflux for 2 h. The solution was concen-
trated in vacuo, the yellow residue was dissolved in THF (5 mL),
and this solution was added dropwise with ice-cooling and stirring
to concd. aq. NH3 (50 mL). After 30 min, the crude product was
filtered off, washed with cold water, dried in air, and recrystallized
from diethyl ether with a small amount of iPrOH to yield a color-
1
less solid (1.24 g, 50%) with m.p. 118Ϫ120 °C. H NMR (CDCl3):
δ ϭ 0.63 (mc, 2 H), 1.00 (mc, 2 H), 2.57 (s, 2 H), 3.79 (s, 3 H), 4.46 temperature for 2 h, (MeO)2SO2 (0.50 mL, 0.65 g, 5.3 mmol) was
(s, 2 H), 5.79 (br. s, 1 H), 6.86 (br. s, 1 H), 6.86 (m, 2 H), 7.24 (m, added dropwise, and the suspension was heated at 40 °C for 2 h.
2 H) ppm. 13C NMR (CDCl3): δ ϭ 12.8 (CH2), 40.1 (CH2), 55.1 The excess of NaH was quenched by careful addition of H2O
(MeO), 58.5 (CϪO), 68.8 (CH2O), 113.8 (CH), 129.3 (C and CH), (0.5 mL), the solvent was evaporated in vacuo, and the residue was
159.2 (C), 173.6 (C) ppm. MS (EI): m/z (%) ϭ 235 (0.1) [Mϩ], 121 dissolved in diethyl ether (20 mL) and washed with water (5 mL).
(100) [C8H9Oϩ]. C13H17NO3 (235.28): calcd. C 66.36, H 7.28, N
5.95; found C 65.98, H 7.29, N 5.73.
After the mixture had been dried, the solvent was evaporated and
the product (667 mg, 83%) was isolated by chromatography on
SiO2 (20 g), eluting with hexane/EtOAc (3:1). 1H NMR (CDCl3,
the signals of the major isomer are marked with *): δ ϭ 0.84 (m,
2 H), 1.10 (m, 2 H), 3.78 (s, 3 H), 3.88*/3.89 (s, 3 H), 4.42*/4.44
(s, 2 H), 6.83Ϫ6.91 (m, 2 H), 6.94 (s, 1 H), 7.18Ϫ7.23 (m, 2 H)
ppm. 13C NMR (CDCl3, signals of the major isomer are marked
with *): δ ϭ 13.4*/14.2 (CH2), 55.2 (OMe), 59.0 (CϪO), 61.9*/62.5
(OMe), 69.2*/69.8 (CH2O), 91.1 (CN), 113.6/113.8* (CH), 129.26*/
129.33 (CH) 129.6 (C), 159.2 (C), 163.5 (CH).
2-[1-(4-Methoxybenzyloxy)cyclopropyl]acetonitrile (14a): Trifluo-
roacetic anhydride (0.80 mL, 1.2 g, 5.7 mmol) was added dropwise
with stirring over 3 min to a suspension of the amide 13a (1.21 g,
5.14 mmol) in CH2Cl2 (8 mL) and pyridine (1.00 mL, 0. 978 g,
12.4 mmol). The clear solution was stirred overnight at ambient
temp., diluted with pentane (50 mL), washed with water (20 mL),
1  aq. HCl (10 mL), water (10 mL), satd. aq. NaHCO3 (10 mL),
and brine (10 mL), and then dried. Evaporation of the organic
solvents in vacuo left the almost pure title compound (1.01 g, 90%
yield) as an oil, which was used in the next step without further
purification. 1H NMR (CDCl3): δ ϭ 0.74 (mc, 2 H), 1.06 (mc, 2
2-[1-(Allyloxy)cyclopropyl]acetic Acid (12b): NaH (0.200 g of a 60%
susp. in mineral oil, 5.00 mmol) was added in small portions at 0
°C with stirring to a solution of 11 (2.90 g, 23.0 mmol) in prop-2-
H), 2.72 (s, 2 H), 3.80 (s, 3 H), 4.52 (s, 2 H), 6.88 (m, 2 H), 7.24 en-1-ol (8.00 mL, 6.83 g, 118 mmol). Stirring was continued over-
(m, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 12.6 (CH2), 23.9 (CH2), night at ambient temperature. The alcohol was evaporated in va-
55.1 (MeO), 57.9 (CϪO), 69.6 (CH2O), 113.7 (CH), 117.4 (C), cuo, the residue was dissolved in EtOH (15 mL), and aq. NaOH
129.1 (CH), 129.4 (C), 159.2 (C) ppm. MS (EI): m/z (%) ϭ 217 (2) (30%, 3 mL) was added. After the mixture had been stirred at am-
[Mϩ], 121 (100) [C8H9Oϩ].
bient temp. for 6 h, the volatiles were evaporated in vacuo, water
(50 mL) was added, and the alkaline solution was extracted with
diethyl ether (2 ϫ 30 mL). The aqueous layer was acidified with 2
 aq. HCl and saturated with solid NaCl. The acid 12b was ex-
tracted with diethyl ether (3 ϫ 50 mL) to give a clear oil (3.10 g,
86%), which was used in the next step without further purification.
1H NMR (CDCl3): δ ϭ 0.67 (mc, 2 H), 0.93 (mc, 2 H), 2.62 (s, 2
H), 4.03 (m, 2 H), 5.08Ϫ5.28 (m, 2 H), 5.81Ϫ5.93 (m, 1 H), 8.3
(br. s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 12.5 (CH2), 39.5 (CH2),
59.0 (CϪO), 68.6 (CH2O), 116.7 (CH2), 134.6 (CH), 176.5 (C)
ppm.
(E/Z)-3-Hydroxy-2-[1-(4-methoxybenzyloxy)cyclopropyl]acrylo-
nitrile (15a): Potassium hydride (1.40 g of a 35% susp. in mineral
oil, 12.2 mmol) was washed three times with diethyl ether under N2,
and then suspended in THF (13 mL). This suspension was added in
small portions, with stirring and cooling with ice, to a solution of
methyl formate (3.0 mL, 2.9 g, 49 mmol) and the nitrile 14a (1.00 g,
4.60 mmol) in THF (13 mL). The reaction mixture was stirred at
ambient temperature for 3 h, and water (50 mL) was carefully ad-
ded, followed by AcOH (ca. 1 mL) until the pH value was 4Ϫ5. The
mixture was extracted with CH2Cl2 (5 ϫ 60 mL), and the combined
organic solutions were washed with H2O (2 ϫ 50 mL), dried, and
concentrated in vacuo. The colorless solid was boiled with 20 mL
of diethyl ether, pentane (40 mL) was then added, and the mixture
2-[1-(Allyloxy)cyclopropyl]acetamide (13b): N,NЈ-Carbonyldiimida-
zole (3.54 g, 21.9 mmol) was added in one portion to a stirred solu-
tion of 12b (3.10 g, 19.9 mmol) in anhydrous THF (22 mL). A vig-
556
Eur. J. Org. Chem. 2003, 551Ϫ561

A New and Productive Route to 1-Heteroarylcyclopropanols
FULL PAPER
orous reaction with gas evolution was observed after several se-
conds. After the mixture had been stirred for 2.5 h at 25 °C,
NH4OAc (1.69 g, 22 mmol) was added, and the mixture was stirred
overnight. The solvent was removed, and the residual oil was
treated with ice/water (15 mL). Aq. HCl (3 ) was added to the
slurry of imidazole and the product until the pH was 2. The clear
solution, with traces of a solid, was saturated with NaCl at 0 °C.
ring under N2 for 20 h, and the solvent was evaporated in vacuo.
The thick precipitate was suspended in water/diethyl ether (1:1,
15 mL), and aq. HCl (1 ) was added dropwise with stirring at 0
°C until the pH of the aqueous layer reached 7. The precipitate
was removed, washed with cold water (10 mL), dried, and crystal-
lized from anhydrous EtOH (40 mL). The first crop (0.45 g of the
pure 16a) had m.p. 191Ϫ193 °C. A second crop (0.21 g) contained
The precipitated product was extracted with EtOAc (3 ϫ 40 mL). a very small amount of 3·HCl as an impurity. Total yield 0.66 g
The combined organic layers were washed with brine (20 mL) and
dried, and the solvents were evaporated. The semi-solid residue was
triturated with diethyl ether and hexane, kept for 2 h at 0 °C, and
the first crop of the product was filtered off (2.10 g, m.p. 89Ϫ90
°C). A second crop (0.17 g) was obtained after the mother liquor
had been diluted with hexane and kept at Ϫ15 °C. Total yield 2.27 g
(74%). 1H NMR (CDCl3): δ ϭ 0.56 (mc, 2 H), 0.92 (mc, 2 H), 2.48
(59%). 1H NMR (CDCl3): δ ϭ 0.97 (mc, 2 H), 1.21 (mc, 2 H), 3.74
(s, 3 H, OMe), 4.30 (s, 2 H, OCH2), 5.93 (s, 2 H, CH2N), 6.01 (br.
s, 2 H, NH2), 6.81 (d, J ϭ 8.0 Hz, 2 H), 6.92Ϫ7.19 (m, 4 H), 7.14
(d, J ϭ 8.0 Hz, 2 H), 7.26 (dd, J ϭ 4.5 and 7.5 Hz, 1 H, 5-H), 8.28
(s, 1 H, 6Ј-H), 8.58 (dd, J ϭ 1.5 and 4.5 Hz, 1 H, 4-H), 8.94 (dd,
J ϭ 1.5 and 8.0 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ ϭ 11.8
(CH2), 44.7 (d, J ϭ 5.2, NCH2), 55.2 (OMe), 59.0 (CϪO), 69.7
(s, 2 H), 3.99 (m, 2 H), 5.10, 5.14, 5.19 and 5.25 (4 mc, 2 H), (CH2O), 113.4 (C-3a), 113.8 (CH in PMB), 115.2 (C-5ЈЈ in the pyri-
5.77Ϫ5.90 (m, 1 H), 6.1 (br. s, 1 H), 6.8 (br. s, 1 H) ppm. 13C NMR midine ring), 115.2 (CH, d, J ϭ 21.4, C-3Ј), 118.2 (CH, C-5), 124.1
(CDCl3): δ ϭ 12.6 (CH2), 40.2 (CH2), 58.6 (CϪO), 67.9 (CH2O), (d, J ϭ 14.5, C-1Ј), 124.1 (CH, d, J ϭ 3.8, C-5Ј), 129.0 (CH, d,
116.9 (CH2), 134.2 (CH), 173.8 (C) ppm. IR (KBr): ν˜ ϭ 3349, 3174, J ϭ 4.4, C-4Ј or C-6Ј), 129.1 (d, J ϭ 8.8, C-6Ј or C-4Ј), 129.4 (C
3094, 3014, 2856, 1668, 1634, 1460, 1414, 1302, 1262, 1175, 1137,
in PMB), 129.8 (CH in PMB), 133.1 (CH, C-4), 141.7 (C-3), 149.2
1117, 1048, 1026. C8H13NO2 (155.19): calcd. C 61.91, H 8.44, N (CH, C-6), 151.5 (C-7a), 154.0 (CH in the pyrimidine ring), 159.3
9.02; found C 61.77, H 8.13, N 9.07.
(C), 160.1 (C), 160.1 (d, J ϭ 247, CF), 169.9 (C) ppm. IR (KBr):
ν˜ ϭ 3487, 3281, 3150, 1631, 1586, 1543, 1514, 1491, 1475, 1438,
1287, 1247, 1228, 1166, 1094, 1036. MS (ESI, positive ions): m/z
(%) ϭ 993 (12) [2 M ϩ Hϩ], 519 (13) [M ϩ Naϩ], 497 (100) [M ϩ
Hϩ]. C28H25FN6O2 (496.55): calcd. C 67.73, H 5.07, N 16.92;
found C 67.74, H 5.17, N 16.98.
2-[1-(Allyloxy)cyclopropyl]acetonitrile (14b): Compound 14b was
prepared from 13b (2.00 g, 12.9 mmol) and trifluoroacetic anhyd-
ride (1.97 mL, 2.96 g, 14.2 mmol) as described for 14a, in quantitat-
ive yield (1.80 g) and as an oil (Rf ϭ 0.3 on SiO2 with CH2Cl2 as
eluent); it was used in the next step without further purification.
1H NMR (CDCl3): δ ϭ 0.72 (mc, 2 H), 1.02 (mc, 2 H), 2.74 (s, 2
H), 4.07 (m, 2 H), 5.14, 5.19, 5.25 and 5.32 (4 mc, 2 H), 5.80Ϫ5.93
(m, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 12.6 (CH2), 24.0 (CH2),
58.2 (CϪO), 69.0 (CH2O), 116.9 (CH2), 117.4 (CN), 134.2 (CH)
ppm.
3-{5-[1-(Allyloxy)cyclopropyl]-4-aminopyrimidin-2-yl}-1-(2-fluoro-
benzyl)-1H-pyrazolo[3,4-b]pyridine (16b): Compound 16b was pre-
pared as described for 16a, starting from 4-All (2.10 g, 11.7 mmol)
and 3·HCl (5.12 g, 16.7 mmol) in anhydrous ketone-free EtOH
(40 mL), to which EtONa (1.04 , 16 mL) was added. Crystalliza-
tion from anhydrous EtOH yielded the pure title compound
(1.80 g) with m.p. 193Ϫ194 °C. A second crop (0.44 g) of 16b was
obtained after chromatographic purification of the residue from the
mother liquor on Al2O3 (100 g), eluting with CH2Cl2. Total yield
(E/Z)-2-[1-(Allyloxy)cyclopropyl]-3-methoxyacrylonitrile
(4-All):
KH (3.98 g of a 35% susp. in mineral oil, 34.8 mmol) was washed
with anhydrous benzene (3 ϫ) and suspended in THF. This suspen-
sion was added in small portions at 0 °C and under N2 to a stirred
solution of methyl formate (8.50 mL, 8.25 g, 0.138 mol) and 14b
(1.80 g, 13.1 mmol) in THF (30 mL). The mixture was stirred at
ambient temperature until the evolution of H2 ceased, and 18-
crown-6 (0.3 g) was added, followed by (MeO)2SO2 (1.05 mL,
1.40 g, 11.1 mmol). The suspension was stirred at ambient temper-
ature for an additional 1 h, and then at 40 °C for 2 h. It was then
filtered, and the filtrate was concentrated in vacuo, diluted with
diethyl ether (100 mL), washed with water (15 mL) and brine
(20 mL), and dried. TLC (CH2Cl2/MeOH, 20:1) revealed only 2
UV-active, closely positioned spots, Rf ഠ 0.8. Concentration left an
oil (2.15 g, 92%), which according to the NMR spectra was the title
compound with traces of 18-crown-6 (δ ϭ 3.95 ppm) as an impur-
ity. This substance was used in the condensation reactions without
1
2.24 g (46%). H NMR (CDCl3): δ ϭ 0.96 (mc, 2 H), 1.20 (mc, 2
H), 3.89 (dt, J ϭ 5.7 and 1.3 Hz, 2 H, OCH2), 5.08, 5.13, 5.15 and
5.21 (4 mc, 2 H, CH2ϭ), 5.74Ϫ5.89 (m, 3 H, NH2, CHϭ), 5.96 (s,
2 H, NCH2), 6.89Ϫ7.07 (m, 3 H), 7.14Ϫ7.21 (m, 1 H), 7.24 (dd,
J ϭ 4.5 and 8.1 Hz, 1 H, 5-H), 8.23 (s, 1 H, 6Ј-H), 8.58 (dd, J ϭ
1.5 and 4.5 Hz, 1 H, 4-H), 8.94 (dd, J ϭ 1.5 and 8.0 Hz, 1 H, 6-
H) ppm. 13C NMR (CDCl3): δ ϭ 11.8 (CH2), 44.7 (d, J ϭ 5.1,
NCH2), 59.1 (CϪO), 68.9 (CH2O), 113.3 (C-3a), 115.23 (CH, d,
J ϭ 21.1, C-3Ј), 115.25 (C-5ЈЈ in the pyrimidine ring), 117.3
(CH2ϭ), 118.2 (CH, C-5), 124.08 (CH, d, J ϭ 3.6, C-5Ј), 124.13
(d, J ϭ 14.5, C-1Ј), 128.9 (CH, d, J ϭ 3.8, C-4Ј or C-6Ј), 129.1 (d,
J ϭ 7.9, C-6Ј or C-4Ј), 133.2 (CH, C-4), 134.1 (CHϭ), 141.7 (C-
3), 149.2 (CH, C-6), 151.6 (C-7a), 154.0 (CH in the pyrimidine
ring), 160.1 (C), 160.1 (d, J ϭ 247, CF), 163.0 (C) ppm. IR (KBr):
ν˜ ϭ 3481, 3282, 3154, 3017, 1632, 1585, 1544, 1491, 1478, 1288,
1229. MS (EI): m/z (%) ϭ 416 (39) [Mϩ], 387 (100) [Mϩ Ϫ Et], 347
(32), 109 (82) [C7H6Fϩ]. C23H21FN6O (416.46): calcd. C 66.33, H
5.08, N 20.18; found C 65.82, H 5.04, N 20.12.
1
further purification. H NMR (CDCl3, the signals of a major iso-
mer are marked with *): δ ϭ 0.82 (m, 2 H), 1.06 (m, 2 H), 3.88*/
3.89 (s, 3 H, MeO), 3.98*/4.00 (mc, 2 H, CH2O), 5.10Ϫ5.28 (m, 2
H, CH2ϭ), 5.80Ϫ5.96 (m, 1 H, CHϭ), 6.89/6.92* (s, 1 H, CHϭ)
ppm. 13C NMR (CDCl3, the signals of a major isomer are marked
with *): δ ϭ 13.3*/14.1 (CH2), 58.5*/58.9 (OMe), 61.9*/62.6
(CϪO), 68.3*/69.0 (CH2O), 91.1 (CN), 115.9/116.7* (C), 116.8
(CH2), 134.2*/134.5 (CH), 162.8/163.3* (CH) ppm.
Treatment of 16a with Trityl Tetrafluoroborate To Yield Compound
3-Tr: A solution of the p-methoxybenzyl ether 16a (115 mg,
0.232 mmol) and Ph3CBF4 (148 mg, 0.448 mmol) in anhydrous
3-(4-Amino-5-{1-[(4-methoxybenzyl)oxy]cyclopropyl}pyrimidin-2- CH2Cl2 (15 mL) was stirred overnight at ambient temp., and then
yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (16a): A solution
of EtONa (1.04 , 4 mL) was added to a solution of 3·HCl (1.28 g,
4.18 mmol) and 4-PMB (0.585 g, 2.26 mmol) in anhydrous ketone-
free EtOH (20 mL). The mixture was heated under reflux with stir-
heated under reflux for 5 h. It was diluted with CH2Cl2 (25 mL),
washed with sat. aq. NaHCO3 (10 mL), dried, and concentrated,
and the residue was placed on Al2O3 (20 g, activity grade II). Elu-
tion with CH2Cl2 gave 3-Tr (Rf ϭ 0.2, 102 mg, 87%) as a white
Eur. J. Org. Chem. 2003, 551Ϫ561
557

V. N. Belov, A. I. Savchenko, V. V. Sokolov, A. Straub, A. de Meijere
FULL PAPER
foam. Crystallization from EtOH/CH2Cl2 gave an analytical Al2O3, eluting with CH2Cl2/MeOH (100:1), gave (Z)-17 (220 mg,
sample with m.p. 186 °C. 1H NMR (CDCl3, two isomers in a ratio
of ca. 5:1, the signals of the major one are marked *): δ ϭ 4.82
53%) as a colorless solid, which was used in the last step without
further purification. H NMR (CDCl3): δ ϭ 1.03 (mc, 2 H), 1.29
1
(br. s, 2 H, NH2), 5.63*/5.66 (s, 2 H, NCH2), 6.92Ϫ7.08 (m, 3 H), (mc, 2 H), 1.51 (dd, J ϭ 6.9 and 1.8 Hz, 3 H), 4.49 (quint, J ϭ 6.7,
7.13Ϫ7.28 (m, 12 H), 7.38Ϫ7.42 (m, 5 H), 8.47/8.51* (dd, J ϭ 1.8 1 H, CHϭ), 5.79 (s, 2 H, NH2), 5.96 (s, 2 H, NCH2), 6.05 (dq, J ϭ
and 4.6 Hz, 1 H, 6Ј-H), 8.59/8.89* (br. d/dd, J ϭ 8.0/1.8 and 8.0,
1 H) ppm. IR (KBr): ν˜ ϭ 3478, 3377, 3052, 3028, 1638, 1586, 1571,
6.3 and 1.7 Hz, 1 H, OCHϭ), 6.92Ϫ7.10 and 7.18Ϫ7.28 (2 m, 5
H, 5-H and 4 H in o-FC6H4), 8.26 (s, 1 H, 6Ј-H), 8.58 (dd, J ϭ 1.6
1483, 1446, 1296, 1264, 1236, 1171, 1133, 1031, 1016. MS (EI): and 4.5 Hz, 1 H, 4-H), 8.94 (dd, J ϭ 1.6 and 8.0 Hz, 1 H, 6-H)
m/z (%) ϭ 511 (100) [Mϩ], 497 (17), 418 (16), 258 (22), 243 (57) ppm. 13C NMR (CDCl3): δ ϭ 9.2 (CH3), 11.4 (CH2), 44.7 (d, J ϭ
[Ph3Cϩ], 182 (23), 165 (22), 109 (16). C33H26FN5 (511.61): calcd. 5.1, NCH2), 59.8 (CϪO), 104.4 (CHϭ), 113.3 (C-3a), 115.20 (CH,
C 77.47, H 5.12, N 13.69; found C 77.74, H 5.26, N 13.44.
d, J ϭ 21.1, C-3Ј), 115.23 (C-5ЈЈ in the pyrimidine ring), 118.2 (CH,
C-5), 123.9 (d, J ϭ 3.6, C-1Ј), 124.1 (CH, d, J ϭ 3.8, C-5Ј), 128.9
(CH, d, J ϭ 3.8, C-4Ј or C-6Ј), 129.1 (d, J ϭ 7.9, C-6Ј or C-4Ј),
133.2 (CH, C-4), 134.1 (CHϭ), 141.6 (C-3), 142.0 (OCHϭ), 149.2
(CH, C-6), 151.5 (C-7a), 154.0 (CH in the pyrimidine ring), 160.1
(d, J ϭ 247, CF), 160.2 (C) ppm. MS (EI): m/z (%) ϭ 416 (19)
[Mϩ], 414 (59), 362 (48), 347 (95), 321 (30), 251 (16), 226 (12),
109 (100).
3-(4-Amino-5-propanoylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridine (18) and 3-[4-Amino-5-(3-ethoxypropanoyl)-
pyrimidin-2-yl]-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (19):
Pd/C (30 mg, 10% Pd in the oxidized form, Merck) in EtOH (6 mL)
was saturated with hydrogen by passing a slow stream of H2
through the suspension for 2 h. The mixture was heated under re-
flux under Ar for 2 h, and 16b (110 mg, 0.264 mmol) was then ad-
ded, followed by aq. HCl (1 , 0.5 mL), and heating was continued (Z)-3-[4-Amino-5-(1-hydroxycyclopropyl)pyrimidin-2-yl]-1-(2-
for 40 h. The catalyst was removed by filtration, washing with hot
EtOH (30 mL), and the solvent was evaporated. The residue was
fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (Metabolite 1-OH). Hy-
drolysis of the Propenyl Ether (Z)-17: Aq. HCl (0.5 , 2.0 mL,
separated on Al2O3 (50 g) eluting with CH2Cl2. The substance 1.0 mmol) was added to
(75 mg) with the same Rf value as the starting material (0.8, 0.529 mmol) in MeOH (2 mL), and the mixture was heated at 55
CH2Cl2/MeOH, 60:1) turned out to be a 1:2 mixture (molar ratio) °C for 1.5 h. At first, (Z)-17 dissolved, and the product 1-OH then
of 16b and 18. Crystallization from EtOH gave the pure compound precipitated gradually. Most of the methanol was evaporated, the
18 (45 mg) with m.p. 219Ϫ220 °C in 64% yield (based on converted residue was neutralized with aq. NaOH (1 ), and the mixture was
16b). 1H NMR (CDCl3): δ ϭ 1.24 (t, J ϭ 7.2 Hz, 3 H), 3.00 (q,
extracted with EtOAc (3 ϫ 50 mL). The combined organic layers
a suspension of (Z)-17 (220 mg,
J ϭ 7.2 Hz, 2 H), 5.97 (s, 2 H, NCH2), 6.11 (br. s, 1 H, NH), were washed with brine, Al2O3 (20 g) was added, and the solvent
6.95Ϫ7.08 (m, 3 H), 7.15Ϫ7.30 (m, 2 H), 8.60 (dd, J ϭ 1.5 and 4.5 was evaporated. CH2Cl2 was added to the residue, and the suspen-
Hz, 1 H, 4-H), 8.82 (br. s, 1 H, NH), 8.91 (dd, J ϭ 1.5 and 8.0 Hz,
sion was concentrated to dryness once more. The residue was
placed on a column prepacked with Al2O3 (100 g) and eluted with
1 H, 6-H), 9.04 (s, 1 H, 6Ј-H) ppm. 13C NMR (CDCl3): δ ϭ 8.3
(CH3), 31.7 (CH2), 45.0 (d, J ϭ 2.6, NCH2), 110.0 (C-3a), 115.3 CH2Cl2/MeOH (50:1). The crude product was isolated as a color-
(CH, d, J ϭ 21.4, C-3Ј), 115.6 (C-5ЈЈ in the pyrimidine ring), 118.7 less solid (170 mg). Recrystallization from MeOH gave the pure
(CH, C-5), 123.8 (C, d, J ϭ 14.5, C-1Ј), 124.1 (d, J ϭ 3.8, C-5Ј), metabolite 1-OH (130 mg, 65%), m.p. 208Ϫ213 °C. The product
129.1 (CH, d, J ϭ 3.8, C-4Ј or C-6Ј), 129.2 (d, J ϭ 6.9, C-6Ј or C-
4Ј), 133.1 (CH, C-4), 140.9 (C-3), 149.4 (CH, C-6), 151.6 (C-7a),
159.6 (CH in the pyrimidine ring), 160.1 (d, J ϭ 247, CF), 162.4
(C), 200.9 (C) ppm. MS (EI): m/z (%) ϭ 376 (100) [Mϩ], 347 (42)
[Mϩ Ϫ Et], 281 (9), 226 (10), 109 (38). The substance with the
lower Rf value (0.7, CH2Cl2/MeOH, 60:1) was identified as 19
(21 mg), yield 25% (based on converted 16b), m.p. 174 °C (dec.,
was in all respects identical to the material isolated from rat hepato-
cyte suspensions.[1] 1H NMR ([D4]MeOH): δ ϭ 0.93 (mc, 2 H), 1.07
(mc, 2 H), 5.87 (s, 2 H, NCH2), 7.03Ϫ7.13 (m, 3 H), 7.14Ϫ7.21 (m,
1 H), 7.24 (dd, J ϭ 4.5 and 8.1 Hz, 1 H, 5-H), 8.14 (s, 1 H, H-6Ј),
8.56 (dd, J ϭ 1.5 and 4.5 Hz, 1 H, 4-H), 9.04 (dd, J ϭ 1.5 and 8.0
Hz, 1 H, 6-H) ppm. 13C NMR ([D6]DMSO): δ ϭ 12.8 (CH2), 44.2
(d, J ϭ 3.8, NCH2), 51.6 (CϪO), 114.8 (C-3a), 115.7 (CH, d, J ϭ
20.7, C-3Ј), 117.1 (C-5ЈЈ in the pyrimidine ring), 118.5 (CH, C-5),
1
EtOH). H NMR (CDCl3): δ ϭ 1.19 (t, J ϭ 7.0 Hz, 3 H), 3.23 (t,
J ϭ 6.3 Hz, 2 H), 3.54 (q, J ϭ 7.0 Hz, 2 H), 3.85 (t, J ϭ 6.3 Hz, 2 124.2 (d, J ϭ 14.5, C-1Ј), 124.8 (CH, d, J ϭ 3.8, C-5Ј), 130.1 (CH,
H), 5.97 (s, 2 H, NCH2), 6.13 (br. s, 1 H, NH), 6.92Ϫ7.08 (m, 3 d, J ϭ 7.5, C-4Ј or C-6Ј), 130.3 (d, J ϭ 4.4, C-6Ј or C-4Ј), 133.5
H), 7.15Ϫ7.30 (m, 2 H), 8.59 (dd, J ϭ 1.5 and 4.5 Hz, 1 H, 4-H),
8.80 (br. s, 1 H, NH), 8.92 (dd, J ϭ 1.5 and 8.0 Hz, 1 H, 6-H), in the pyrimidine ring), 158.9 (C), 160.1 (d, J ϭ 247, CF), 163.0
9.06 (s, 1 H, 6Ј-H) ppm. 13C NMR (CDCl3): δ ϭ 15.8 (CH3), 38.7
(C) ppm. IR (KBr): ν˜ ϭ 3482, 3288, 3155, 3017, 1632, 1545, 1491,
(CH2), 45.0 (d, J ϭ 5.3, NCH2), 65.5 (CH2O), 66.6 (CH2O), 110.4 1458, 1230. MS (EI): m/z (%) ϭ 376 (100) [Mϩ], 347 (39) [Mϩ
(C-3a), 115.3 (CH, d, J ϭ 19.5, C-3Ј), 115.7 (C-5ЈЈ in the pyrimid-
Et], 281 (10) [Mϩ Ϫ C5H5NO], 226 (9), 109 (40) [C7H6Fϩ].
ine ring), 118.7 (CH, C-5), 123.8 (C, d, J ϭ 14.5, C-1Ј), 124.1 (d, C20H17FN6O (376.40): calcd. C 63.82, H 4.55; found C 63.66, H
(CH, C-4), 141.7 (C-3), 149.4 (CH, C-6), 151.0 (C-7a), 152.8 (CH
Ϫ
J ϭ 3.8, C-5Ј), 129.1 (CH, d, J ϭ 3.8, C-4Ј or C-6Ј), 129.3 (d, J ϭ
8.2, C-6Ј or C-4Ј), 133.1 (CH, C-4), 140.8 (C-3), 149.4 (CH, C-6),
151.6 (C-7a), 160.1 (CH in the pyrimidine ring), 160.1 (d, J ϭ 247,
CF), 162.5 (C), 198.5 (C) ppm.
4.52.
Direct Cleavage of Allyl Ether 16b with Grignard Reagents in the
Presence of Ti(OiPr)4: A solution of cyclohexylmagnesium bromide
in diethyl ether (1.9 , 0.58 mL, 1.1 mmol) was added at 10 °C to
a solution of 16b (434 mg, 1.04 mmol) in THF (25 mL), followed
by Ti(OiPr)4 (304 mg, 1.07 mmol). The dropwise addition of cyclo-
(Z)-3-(4-Amino-5-{1-[(1-propenyl)oxy]cyclopropyl}pyrimidin-2-yl)-1-
(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine
[(Z)-17]:
tBuOK
(224 mg, 2.00 mmol) was added under N2 at ambient temp. to a hexylmagnesium bromide was then continued at 10 °C until
solution of 16b (416 mg, 1.00 mmol) in anhydrous DMSO 2.32 mL (4.41 mmol) had been added over 1 h, and the mixture
(4.5 mL), and the mixture was heated at 90 °C for 1.5 h. After was then stirred for an additional 2 h. It was poured into a 1:1
cooling, it was diluted with ice/water (15 mL) and extracted with
EtOAc (3 ϫ 50 mL). The resulting brown solution was washed with
water (10 mL) and brine (10 mL) and dried. Chromatography on
mixture of brine and cold water (50 mL), the aqueous mixture was
extracted with EtOAc (4 ϫ 80 mL), and the combined organic
layers were washed with brine and dried. After evaporation of the
558
Eur. J. Org. Chem. 2003, 551Ϫ561

A New and Productive Route to 1-Heteroarylcyclopropanols
FULL PAPER
solvent, the solid residue was treated successively with pentane (2
ϫ 5 mL), pentane/diethyl ether (1:1, 5 mL), and diethyl ether
(5 mL) in an ultrasound bath to get rid of dicyclohexyl as the main
impurity. Crystallization from MeOH afforded 1-OH [Rf ϭ 0.14
NMR (CDCl3): δ ϭ 0.86 (mc, 2 H), 1.12 (mc, 2 H), 3.82 (s, 3 H,
OMe), 3.85 (dt, J ϭ 5.6 and 1.2 Hz, 2 H, OCH2), 5.08Ϫ5.22 (m, 2
H, CH2ϭ), 5.78Ϫ5.92 (m, 1 H, CHϭ), 5.99 (br. s, 2 H, NH2), 7.00
(s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 12.2 (CH2), 51.2 (OMe),
(hexane/EtOAc) or 0.23 (hexane/EtOAc/EtOH, 4:1:0.5, 270 mg, 58.6 (CϪO), 68.7 (CH2O), 116.9 (CH2ϭ), 128.0 (CH, C-5), 130.8
69%]. A lower yield of 1-OH (44%) was observed in an analogous
(C-4), 134.3 (CHϭ), 153.6 (C), 158.0 (C), 164.9 (C) ppm. IR (KBr):
ν˜ ϭ 3453, 3339, 3077, 3017, 2924, 1675, 1607, 1553, 1476, 1448,
experiment with ethylmagnesium bromide in place of cyclohexyl-
magnesium bromide. Compound 20 was isolated as a by-product 1295, 1217, 1027. MS (EI): m/z (%) ϭ 253 (39) [Mϩ], 224 (12) [Mϩ
in 12% yield after chromatographic purification of the crude prod-
Ϫ Et], 184 (24), 180 (37), 170 (100), 152 (38). HRMS: calcd. for
C12H15NO3S 253.0773; found 253.0773. 23: Rf ϭ 0.40, yield 32 mg
uct. 20: Rf ϭ 0.31 (hexane/EtOAc/EtOH, 4:1:0.5), m.p. 168Ϫ171
°C. 1H NMR ([D6]DMSO): δ ϭ 0.85 (mc, 2 H), 1.00 (mc, 2 H), (5%) of a colorless oil, which crystallized to a solid with m.p. 35
1
1.29 (t, J ϭ 7.5 Hz, 3 H), 2.92 (q, J ϭ 7.5 Hz, 2 H), 5.77 (s, 2 H, °C. H NMR (CDCl3): δ ϭ 1.38 (t, J ϭ 7.6 Hz, 3 H), 3.04 (q, J ϭ
NCH2), 7.10Ϫ7.40 (m, 4 H), 7.26 (d, J ϭ 7.4 Hz, 1 H, 5-H), 8.16 7.6 Hz, 2 H), 3.88 (s, 3 H, OMe), 7.76 (s, 1 H) ppm. 13C NMR
(s, 1 H, 6Ј-H), 8.82 (d, J ϭ 7.4 Hz, 1 H, 6-H) ppm. 13C NMR
(CDCl3): δ ϭ 15.3 (Me), 23.5 (CH2), 52.5 (OMe), 108.6 (C-3), 113.8
([D6]DMSO): δ ϭ 12.7 (CH2), 13.8 (Me), 31.1 (CH2), 44.0 (d, J ϭ (CN), 131.7 (C-4), 134.0 (CH, C-5), 161.1 (C), 164.8 (C) ppm. IR
3.8, NCH2), 51.6 (CϪO), 112.9 (C-3a), 115.7 (CH, d, J ϭ 21.4, C-
(KBr): ν˜ ϭ 3106, 3063, 2970, 2955, 2229, 1725, 1543, 1446, 1385,
3Ј), 116.9 (C-5ЈЈ in the pyrimidine ring), 117.9 (CH, C-5), 124.3 (d, 1266, 1205, 1169, 1094, 1066. MS (EI): m/z (%) ϭ 195 (50) [Mϩ],
J ϭ 14.5, C-1Ј), 124.8 (CH, d, J ϭ 3.1, C-5Ј), 130.1 (CH, d, J ϭ 180 (100), 164 (59). HRMS: calcd. for C9H9NO2S 195.0354;
8.2, C-4Ј or C-6Ј), 130.4 (d, J ϭ 3.8, C-6Ј or C-4Ј), 133.4 (CH, C-
4), 141.5 (C-3), 151.1 (C-7a), 152.8 (CH in the pyrimidine ring),
160.0 (d, J ϭ 247, CF), 162.1 (C), 162.8 (C), 163.4 (C) ppm. IR
(KBr): ν˜ ϭ 3474, 3286, 3154, 1632, 1545, 1492, 1459, 1231.
found 195.0354.
5-[1-(Allyloxy)cyclopropyl]-2,4-diaminopyrimidine (27): A solution
of sodium methoxide in MeOH (1.52 , 3 mL, 4.56 mmol) was
added to a solution of 4-All (460 mg, 2.57 mmol) and guanidine
Palladium-Promoted Cleavage of Allyl Ether 16b: [Pd(Ph3P)4] hydrochloride (382 mg, 4.00 mmol) in MeOH (3 mL), and the mix-
(8.0 mg, 0.0069 mmol) was added under N2 to a suspension of 16b ture was heated under reflux overnight. Water (5 mL) was added
(22.5 mg, 0.054 mmol), PdCl2 (9.6 mg, 0.054 mmol), and NaOAc to the cooled reaction mixture, and the solvents were evaporated
(10 mg, 0.12 mmol) in AcOH (0.25 mL), followed by lithium p- in vacuo. The solid residue was suspended in cold water (5 mL),
toluenesulfinate (22.4 mg, 0.138 mmol). The reaction mixture was filtered off, washed with cold water, and dried in air to give the
heated with stirring at 50 °C for 1.5 h, EtOAc (5 mL) was added, title compound 27 (500 mg, 87%) as monohydrate with m.p.
and the suspension was passed through a fritted glass filter (No. 128Ϫ129 °C. 1H NMR ([D6]DMSO): δ ϭ 0.71 (mc, 2 H), 0.98
5). The insoluble residue was washed with EtOAc (3 ϫ 5 mL), the
combined filtrates were concentrated to dryness in vacuo, and the
residue was subjected to chromatography on Al2O3 (20 g), eluting
with CH2Cl2 to remove the yellow zone of by-products with higher
retention indices (allyl p-toluenesulfinate and unidentified prod-
ucts); subsequent elution with CH2Cl2/MeOH (100:1) gave 1-OH
(16.0 mg, 79%).
(mc, 2 H), 3.76 (br. d, J ϭ 5.3, 2 H, OCH2), 5.01Ϫ5.20 (m, 2 H,
CH2ϭ), 5.73Ϫ5.84 (m, 1 H, CHϭ), 5.98 (s, 2 H, NH2), 6.1 (br. s,
2 H, NH2), 7.62 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ ϭ 11.8
(CH2), 58.7 (CϪO), 67.5 (CH2O), 103.8 (C-5), 116.2 (CH2ϭ), 135.6
CHϭ), 156.3 (CH, C-6), 163.2 (C), 163.4 (C) ppm. IR (KBr): ν˜ ϭ
3479, 3440, 3319, 3153, 3017, 2908, 1651, 1633, 1598, 1557, 1465,
1330, 1273, 1218, 1106, 1036. MS (CI): m/z (%) ϭ 413 (16) [2 M
ϩ Hϩ], 207 (100) [M ϩ Hϩ]. C10H14N4O·H2O (224.26): calcd. C
53.56, H 7.19, N 24.98; found C 53.79, H 7.20, N 25.19.
4-[1-(Allyloxy)cyclopropyl]-3-amino-1H(2H)-pyrazole (21): A mix-
ture of 4-All (400 mg, 2.23 mmol) and anhydrous N2H4 (200 mg,
6.25 mmol) in MeOH (3 mL) was heated at 85 °C overnight. The 5-[1-(Allyloxy)cyclopropyl]-4-amino-2-mercaptopyrimidine (28): So-
solvent was evaporated, and the residue was subjected to chromato- dium methoxide (2.0 mL of a 1.9  solution in MeOH, 3.8 mmol)
graphy on SiO2 (25 g), eluting with CH2Cl2/MeOH (15:1), to yield was added to a solution of 4-All (460 mg, 2.57 mmol) and thiourea
21 (230 mg, 57%) as a colorless oil, Rf ϭ 0.35Ϫ0.40. 1H NMR (342 mg, 4.50 mmol) in MeOH (6 mL), and the mixture was heated
(CDCl3): δ ϭ 0.76 (mc, 2 H), 1.08 (mc, 2 H), 3.88 (dt, J ϭ 5.6 and
under reflux for 24 h. After the mixture had been cooled in an ice
1.4 Hz, 2 H, OCH2), 5.06Ϫ5.24 (m, 2 H, CH2ϭ), 5.78Ϫ5.92 (m, 1 bath, glacial acetic acid was added dropwise until the pH value was
H, CHϭ), 7.16 (s, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 12.7 (CH2), 5. A precipitate appeared, the suspension was kept at 0 °C for 16 h
55.0 (CϪO), 68.0 (CH2O), 105.4 (C-4), 116.6 (CH2ϭ), 130.0 (CH), and filtered, and the crude product was washed with cold water
134.8 (CHϭ), 152.8 (C-3) ppm. IR (neat): ν˜ ϭ 3429, 3314, 3211,
(2 mL) and MeOH (1 mL). After crystallization from aq. EtOH,
3089, 3012, 2959, 1611, 1585, 1505, 1408, 1225, 1044. MS (CI): the title compound 28 (170 mg, 30%) was obtained as a light brown
m/z (%) ϭ 359 (64) [2 M ϩ Hϩ], 197 (38) [M ϩ NH4ϩ], 180 (100)
solid (decomp. without melting at Ͼ
250 °C). 1H NMR
[M ϩ Hϩ]. HRMS: found 178.1014, calcd. for C9H12N3O [Mϩ
Ϫ
([D6]DMSO): δ ϭ 0.79 (mc, 2 H), 1.02 (mc, 2 H), 3.80 (br. d, J ϭ
5.3, 2 H, OCH2), 5.03Ϫ5.23 (m, 2 H, CH2ϭ), 5.71Ϫ5.86 (m, 1 H,
CHϭ), 6.8 (br. s, 1 H, NH/SH), 7.36 (s, 1 H), 7.8 (br. s, 1 H, NH/
SH), 8.0 (br. s, 1 H, NH/SH) ppm. 13C NMR ([D6]DMSO): δ ϭ
11.8 (CH2), 58.0 (CϪO), 68.1 (CH2O), 106.1 (C-5), 116.2 (CH2ϭ),
135.1 (CHϭ), 141.7 (CH, C-6), 161.8 (C), 179.4 (C) ppm. IR
(KBr): ν˜ ϭ 3407, 3347, 3093, 3043, 2974, 1659, 1567, 1547, 1296,
1234, 1202, 1171, 1040. MS (CI): m/z (%) ϭ 224 (100) [M ϩ Hϩ].
HRMS: calcd. for C10H12N3OS [Mϩ Ϫ H] 222.0701; found
222.0756.
H]: 178.0980.
Methyl 4-[1-(Allyloxy)cyclopropyl]-3-aminothiophene-2-carboxylate
(22) and Methyl 4-Cyano-3-ethylthiophene-2-carboxylate (23): A so-
lution of sodium methoxide (1.52 , 3 mL, 4.56 mmol) in MeOH
was added to a mixture of 4-All (585 mg, 3.27 mmol) and methyl
thioglycolate (0.460 mL, 543 mg, 5.12 mmol). The mixture was
heated under reflux overnight. The blue-black reaction mixture was
filtered through SiO2 (2.5 g), the filter cake was washed with
CH2Cl2 (25 mL), and the filtrate was concentrated in vacuo. The
oily residue was subjected to chromatography on SiO2 (25 g); elu-
3-Amino-4-(1-hydroxycyclopropyl)-1H(2H)-pyrazole
(29):
tion with hexane/EtOAc (5:1) gave 22 (Rf ϭ 0.45, 389 mg, 47%) as [Pd(Ph3P)4] (66 mg, 0.057 mmol) and lithium p-toluenesulfinate
a colorless oil, which crystallized to a solid with m.p. 50 °C. 1H
Eur. J. Org. Chem. 2003, 551Ϫ561
(162 mg, 1.00 mmol) were added under N2 to a suspension of the
559

V. N. Belov, A. I. Savchenko, V. V. Sokolov, A. Straub, A. de Meijere
FULL PAPER
allyl ether 21 (158 mg, 0.882 mmol), PdCl2 (120 mg, 0.677 mmol),
1
(heptane). H NMR (CDCl3): δ ϭ 0.88 (mc, 2 H), 1.10 (mc, 2 H),
and sodium acetate (120 mg, 1.46 mmol) in glacial acetic acid 3.80 (s, 3 H), 5.95 (br. s, 2 H, NH2), 7.00 (s, 1 H) ppm. 13C NMR
(1 mL), and the mixture was heated with stirring at 40 °C for (CDCl3): δ ϭ 13.3 (CH2), 51.2 (MeO), 52.7 (CϪO), 101.2 (C),
40 min. After cooling, it was worked up as described for 1-OH (Pd-
assisted cleavage of 16b). Chromatography on SiO2 (20 g), eluting
126.9 (CH), 134.4 (C), 153.6 (C), 165.0 (C) ppm. IR (KBr): ν˜ ϭ
3465, 3396, 3362, 3341, 3089, 2946, 1677, 1646, 1553, 1476, 1451,
with CH2Cl2/MeOH (15:1 Ǟ 3:1), gave 29·AcOH (125 mg, 71%) 1318, 1290, 1237, 1134, 1102, 1020. MS (EI): m/z (%) ϭ 213 (37)
1
as an oil. H NMR ([D4]MeOH): δ ϭ 0.78 (mc, 2 H), 0.96 (mc, 2
[Mϩ], 184 (12) [Mϩ Ϫ Et], 181 (23), 153 (100), 125 (29), 108 (9),
H), 1.96 (s, 3 H), 7.22 (s, 1 H) ppm. 13C NMR ([D4]MeOH): δ ϭ 97 (36). HRMS: calcd. for C9H11NO3S 213.0460; found 213.0460.
14.7 (CH2), 21.6 (Me), 49.0 (CϪO), 110.4 (C-4), 131.2 (CH), 155.8
2,4-Diamino-5-[1-(methylthio)cyclopropyl]pyrimidine (33): The allyl
(C-3), 178.9 (C) ppm. IR (KBr): ν˜ ϭ 3429, 3335, 3210, 2973, 2935,
ether 27·H2O (125 mg, 0.56 mmol) was dried in vacuo at 110 °C
1645, 1543, 1399, 1224, 1124, 1035, 1011. MS (EI): m/z (%) ϭ 139
for 30 min, until its mass was constant (116 mg). It was dissolved
in anhydrous DMSO (2 mL), potassium tert-butoxide (252 mg,
2.24 mg) was added, and the solution was stirred at 80 °C under
N2 for 50 min, until the spot corresponding to 27 had disappeared.
The reaction mixture was worked up as described above for (Z)-
17. Sulfide 33 (11 mg, 10%) was isolated by column chromato-
graphy on SiO2 (20 g), eluting with EtOAc/MeOH (20:1 Ǟ 10:1),
m.p. 221 °C (iPrOH/heptane). 1H NMR ([D6]DMSO): δ ϭ 0.92
(mc, 2 H), 1.00 (mc, 2 H), 1.93 (s, 3 H), 5.38 (br. s, 2 H, NH2), 5.83
(br. s, 2 H, NH2), 7.54 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ ϭ
13.4 (Me), 14.0 (CH2), 22.0 (CϪS), 106.1 (C), 155.0 (CH), 161.0
(C), 161.3 (C) ppm. IR (KBr): ν˜ ϭ 3455, 3434, 3385, 3135, 3023,
2922, 1657, 1635, 1594, 1555, 1467, 1266, 1186, 1032. MS (EI):
m/z (%) ϭ 196 (24) [Mϩ], 195 (76), 181 (42) [Mϩ Ϫ Me], 153 (22),
149 (100) [Mϩ Ϫ MeS]. MS (ESI, positive ions): m/z (%) ϭ 197
(100) [M ϩ Hϩ]. HRMS: calcd. for C8H12N4S 196.0783; found
196.0783.
(36) [Mϩ], 110 (100) [Mϩ Ϫ Et], 83 (15), 60 (12). HRMS: found
139.0746, calcd. for C9H9N3O: 139.0746.
Methyl 3-Amino-4-propionylthiophene-2-carboxylate (31) and
Methyl
3-Amino-4-{3-[(4-methylphenyl)sulfonyl]propanoyl}thio-
phene-2-carboxylate (32): [Pd(Ph3P)4] (47 mg, 0.041 mmol) and li-
thium p-toluenesulfinate (99 mg, 0.61 mmol) were added under N2
to a suspension of 22 (105 mg, 0.415 mmol), PdCl2 (29 mg,
0.16 mmol), and sodium acetate (31 mg, 0.38 mmol) in acetic acid
(0.5 mL), and the mixture was heated at 48 °C with stirring. After
45 min, the starting material had not yet been consumed, and two
new spots with lower Rf values had appeared on the TLC. After
addition of more PdCl2 (25 mg, 0.14 mmol) and sodium acetate
(29 mg, 0.35 mmol), the reaction was complete within another
15 min. The mixture was worked up as described for 1-OH (Pd-
assisted cleavage of 16b). Chromatography on SiO2 (20 g), eluting
with PE/EtOAc (4:1), first gave the ketone 31 (34 mg, 38%) as an
oil that soon crystallized to a pale yellow solid, m.p. 100 °C (hept-
ane). 1H NMR (CDCl3): δ ϭ 1.19 (t, J ϭ 7.7 Hz, 3 H), 2.86 (q,
J ϭ 7.7 Hz, 2 H), 3.83 (s, 3 H), 7.2 (br. s, 2 H, NH2), 8.01 (s, 1 H)
ppm. 13C NMR (CDCl3): δ ϭ 8.2 (Me), 32.7 (CH2), 51.3 (MeO),
128.3 (C), 138.5 (CH), 154.1 (C), 158.1 (C), 164.4 (C), 196.8 (C)
ppm. IR (KBr): ν˜ ϭ 3469, 3351, 3078, 2982, 2940, 1671, 1646,
1580, 1520, 1447, 1313, 1244, 1209, 1141, 1087, 1072. MS (EI):
m/z (%) ϭ 213 (96) [Mϩ], 184 (100) [Mϩ Ϫ Et], 182 (12), 181 (15),
153 (18), 152 (42). HRMS: calcd. for C9H11NO3S 213.0460; found
213.0460. Further elution gave 32 (45 mg, 30%) as a solid with m.p.
2,4-Diamino-5-(1-hydroxycyclopropyl)pyrimidine (34): Compound
27·H2O (95 mg, 0.42 mmol) was deprotected by treatment with
PdCl2 (43 mg, 0.24 mmol), sodium acetate (43 mg, 0.52 mmol), li-
thium p-toluenesulfinate (76 mg, 0.47 mmol), and (Ph3P)4Pd
(35 mg, 0.03 mmol) in acetic acid (0.60 mL) at 40 °C as described
above for compound 29. The reaction was complete within 35 min.
MeOH (10 mL) was added with stirring to the reaction mixture,
which had solidified into a light brown paste, the inorganic salts
were removed by filtration, and the filter cake was washed with
MeOH (2 ϫ 5 mL). Concentration of the filtrate yielded a yellow
solid, which was subjected to chromatography on Al2O3 (35 g). Elu-
tion with CH2Cl2/MeOH (3:1) gave 38 mg (54%) of 34 as a yellow-
1
175 °C (heptane). H NMR (CDCl3): δ ϭ 2.44 (s, 3 H), 3.29Ϫ3.37
(m, 2 H), 3.44Ϫ3.52 (m, 2 H), 3.83 (s, 3 H), 7.0 (br. s, 2 H, NH2),
7.35 (d, J ϭ 8.0 Hz, 2 H), 7.79 (d, J ϭ 8.0 Hz, 2 H), 8.05 (s, 1 H)
ppm. 13C NMR (CDCl3): δ ϭ 21.6 (Me), 32.1 (CH2), 50.6 (CH2),
51.4 (MeO), 127.5 (C), 128.0 (CH), 130.0 (CH), 135.8 (C), 139.1
(CH), 145.1 (C), 154.0 (C), 164.2 (C), 190.9 (C) ppm. IR (KBr):
ν˜ ϭ 3465, 3351, 2950, 1692, 1651, 1597, 1527, 1448, 1301, 1259,
1222, 1148, 1124, 1084. HRMS: m/z (%) ϭ 367 (100) [Mϩ], 262
(8), 213 (25), 184 (27), 180 (96), 152 (23). MS (HR-EI): calcd. for
C16H17NO5S2 367.0548; found 367.0548.
1
ish solid, m.p. 202Ϫ203 °C. H NMR ([D6]DMSO): δ ϭ 0.66 (mc,
2 H), 0.83 (mc, 2 H), 5.52 (s, 1 H, OH), 5.82 (s, 2 H, NH2), 6.1 (br.
s, 2 H, NH2), 7.59 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ ϭ 12.8
(CH2), 51.4 (CϪO), 108.7 (C-5), 154.4 (CH), 162.8 (C), 163.4 (C)
ppm. IR (KBr): ν˜ ϭ 3435, 3327, 3155, 3081, 3006, 1657, 1635,
1598, 1557, 1464, 1446, 1347, 1209, 1025. MS (EI): m/z (%) ϭ 166
(23) [Mϩ], 165 (100), 137 (68) [Mϩ Ϫ Et], 123 (8), 110 (100).
HRMS: calcd. for C7H10N4O 166.0855; found 166.0855.
Methyl 3-Amino-4-(1-hydroxycyclopropyl)thiophene-2-carboxylate
(30): Ti(OiPr)4 (0.147 mL, 142 mg, 0.500 mmol) was added drop-
wise with stirring, at room temperature, to a solution of 22 (64 mg,
0.25 mmol) in anhydrous diethyl ether (5 mL). Cyclohexylmagnes-
ium bromide (1.13 mL of 1.33  solution in THF, 1.5 mmol) was
then added very slowly (over ca. 4 h). The product spot was detect-
able by TLC after ca. 0.6 mL of the Grignard reagent had been
added. The dark reaction mixture was stirred overnight at room
temperature, satd. aq. NH4Cl (2 mL) and EtOAc (10 mL) were then
added, and the whole mixture was filtered through Celite (2 mL).
The filter cake was washed with EtOAc (3 ϫ 5 mL), the organic
layer was separated, and the solvents were evaporated in vacuo.
The brown, oily residue was subjected to chromatography on SiO2
(8 g), eluting with a hexane/EtOAc mixture (2:1), to yield cyclopro-
panol 30 (24.5 mg, 46%) as a colorless solid, m.p. 102Ϫ103 °C
Acknowledgments
This work was supported by BAYER AG, a COPERNICUS grant,
and the Fonds der Chemischen Industrie. The authors are grateful
to Dr. B. Knieriem for his careful reading of the final version of
this manuscript.
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