Regioselective rapid analogue syntheses of 1-methyl-3,5-diarylpyrazoles via palladium-catalysed coupling to 3(5)-pyrazolyl nonaflates

Article abstract of DOI:10.1055/s-2004-820020

Regioselective rapid analogue syntheses of 1-methyl-3,5-diarylpyrazoles were developed, based on Pd-catalysed couplings to 1-methyl-3(5)-arylpyrazole nonaflates, which offered an advantage in hydrolytic stability over the corresponding triflates. The new bifunctional reagent 1-methyl-3-bromo-pyrazol- 5-yl nonaflate underwent highly chemoselective Pd-catalysed couplings to the nonaflate, followed by Suzuki couplings to the bromide, allowing sequential, regioselective introduction of the two aryl substituents.

Full text of DOI:10.1055/s-2004-820020

LETTER
795
Regioselective Rapid Analogue Syntheses of 1-Methyl-3,5-diarylpyrazoles via
Palladium-catalysed Coupling to 3(5)-Pyrazolyl Nonaflates
Rapid
A
nalogu
y
e
Syntheses
l
of 1-M
v
ethyl-3,5-dia
i
rylpyra
e
zoles Bourrain, Mark Ridgill, Ian Collins*1
Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park,
Harlow, Essex CM20 2QR, UK
Fax +44(2087)707899; E-mail: Ian.Collins@icr.ac.uk
Received 14 November 2003
F
F
Abstract: Regioselective rapid analogue syntheses of 1-methyl-
3,5-diarylpyrazoles were developed, based on Pd-catalysed cou-
plings to 1-methyl-3(5)-arylpyrazole nonaflates, which offered an
advantage in hydrolytic stability over the corresponding triflates.
The new bifunctional reagent 1-methyl-3-bromo-pyrazol-5-yl non-
aflate underwent highly chemoselective Pd-catalysed couplings to
the nonaflate, followed by Suzuki couplings to the bromide, allow-
ing sequential, regioselective introduction of the two aryl substitu-
ents.
OMe
b
O
O
CO2Me
1
2 (72%)
a
c
F
F
OH
OH
Key words: regioselectivity, chemoselectivity, palladium, cross-
coupling, heterocycles
N
N
N
N
Me
Me
3 (84%)
4 (60%)
d
d or e
Substituted pyrazoles are important constituents of bio-
logically active synthetic compounds.2 As part of a medic-
inal chemistry program, we required an efficient,
regioselective synthetic route to variously substituted 1-
methyl-3,5-diarylpyrazoles. In particular, we wished to be
able to introduce 1-methyl-3(5)-arylpyrazole moieties to
more complex substituted arylboronates using palladium-
catalysed cross-couplings at a late stage in the sequence.
There are many reported methods for the regioselective
formation of N-alkyl pyrazoles2 and recently methods
have become available for Pd-catalysed cross-couplings
to N-alkyl- and N-aryl-3(5)-halopyrazoles.3,4 Descriptions
of cross-coupling reactions to pyrazole trifluoromethane-
sulfonates (triflates)5 are scarce, however, and there are no
reports concerning pyrazole nonafluorobutanesulfonates
(nonaflates).
F
F
OSO2C4F9
OSO2R
N
N
N
N
Me
Me
5 (89%)
6a R = CF3 (96%)
6b R = C4F9 (88%)
f
f
F
F
Ar
Ar
N
N
N
N
Me
Me
7a–d
8a–d
Scheme 1 Reaction conditions: (a) NH2NHMe, MeOH, r.t.; (b)
Ph3P=O, (CF3CO)2O, Et3N, 1,2-dichloroethane, 0 °C, reflux; (c)
NH2NHMe, EtOH, H2O, 60 °C; (d) NaHMDS, C4F9SO2F, THF, 0 °C;
(e) (CF3SO2)2, pyridine, –20 °C to r.t.; (f) ArB(OH)2, Pd(PPh3)4,
Na2CO3, DMF, 100 °C.
Our initial studies targeted 3- and 5-(4-fluorophenyl)pyra-
zoles. The condensation of methylhydrazine with methyl
4-fluorobenzoylacetate 1 gave predominantly a single
pyrazole 3,6 which was conveniently isolated in pure form
by crystallisation from the reaction mixture (43% yield).
Column chromatography of the mother liquors allowed
the isolation of further pure product 3 (41%) and a minor
product 4 (4%, Scheme 1). The regiochemistry of the mi-
nor product was demonstrated by the observed NOE be-
tween the N-methyl group and the fluoroaromatic ring
(Figure 1). To prepare synthetically useful quantities of
the regioisomer 4, the alternative cyclocondensation of
methylhydrazine and b-arylacetylenic esters was investi-
gated.6,7 Thus, methyl 4-fluorobenzoylacetate 1 was dehy-
drated to the alkynyl ester 2 in good yield.8 Other methods
for the production of 2, e.g. Pd-catalysed coupling of 1-
iodo-4-fluorobenzene and TMS-acetylene, followed by
lithiation and quenching with methyl chloroformate,9
were successful but gave lower overall yields. The reac-
tion of ethyl phenylpropionate and MeNHNH2 in aqueous
MeOH is known to give a mixture of pyazoles where the
regiochemistry corresponding to 3 dominates.7a However,
the reaction of the methyl ester is reported to lead to the
alternative regioisomer.7b In agreement with this, the
methyl ester 2 gave predominantly the desired pyrazole 4
on treatment with MeNHNH2 in warm aqueous EtOH (4:3
ca. 2:1 in crude mixture). A strong effect of the size of the
ester group on the regioselectivity of the condensation
SYNLETT 2004, No. 5, pp 0795–0798
0
2.
0
4.
2
0
0
4
Advanced online publication: 04.03.2004
DOI: 10.1055/s-2004-820020; Art ID: D28703ST
© Georg Thieme Verlag Stuttgart · New York

796
S. Bourrain et al.
LETTER
was observed: When the analogous isopropyl ester was The nonaflate 5 underwent complete conversion upon re-
subject to the same conditions, the condensation favoured action with electron-rich or electron-poor arylboronic ac-
formation of 3 (3:4 85:15 in crude mixture).
ids, and the products 7a–d were isolated in reasonable
yields after automated normal-phase HPLC purification11
with UV-triggered fraction collection. The regiochemis-
try of the products 7 was demonstrated by the observed
NOEs from the N-methyl group (e.g. 7b, Figure 1). In
contrast, the reactions of the nonaflate 6b reached only
30–60% conversion under similar conditions, as shown by
HPLC-MS analysis of the crude reaction mixtures, lead-
ing to substantially lower yields of the products 8a–d.
This perhaps indicates relative destabilisation, and there-
fore greater reactivity, of the nonaflate 5 by 1,2-steric re-
pulsion from the adjacent N-methyl group. The use of
higher catalyst loadings or microwave irradiation at
150 °C did not significantly improve the reactions of 6b,
and further optimisation was not attempted. However,
more efficient couplings to the nonaflate 6b were possible
when boronate esters, in particular aryl neopentylglycola-
toboronates, were used as the coupling partners (e.g.
Equation 1), giving complete conversion of the nonaflate
and excellent yield of the products such as 9.
The pyrazole 4 was conveniently isolated (60% yield,
>99% purity) by crystallisation from the cooled mixture,
the mother liquors containing mainly the regioisomer 3
(typically 90% purity). The pyrazoles 3 and 4 were readily
prepared on a large scale (10–30 g) using these proce-
dures.
While the conversion of N-aryl hydroxypyrazoles related
to 3 and 4 to the corresponding bromopyrazoles has been
demonstrated,4a for ease of synthesis, we chose to investi-
gate the coupling reactions of the sulfonate derivatives.
The triflate 6a was readily prepared in high yield from the
pyrazole 4 [pyridine, (CF3SO2)2O, 96%] and the Pd-catal-
ysed coupling of 6a to electron-rich aryl pinacolatobor-
onates (not shown) was explored. The triflate 6a proved
susceptible to hydrolysis to 4 under aqueous conditions or
in the presence of strong bases (e.g. Cs2CO3). Although
successful coupling was achieved under non-aqueous
conditions with a weak base [Pd(PPh3)4, Na2CO3, DMF,
100 °C, maximum 70–80% isolated yields] the reaction
was capricious, with variable yields and degrees of cleav-
age to 4 observed. The instability of the triflate under the
coupling conditions suggested the use of the nonaflates,
which were originally proposed as hydrolytically more
stable alternatives to triflates.10 Accordingly, the hydrox-
ypyrazoles 3 and 4 were deprotonated with NaHMDS and
reacted smoothly with nonaflyl fluoride to generate the
nonaflates 5 and 6b in high yield. Under the optimum
reaction conditions devised for 6a, minimal cleavage to
the hydroxypyrazoles (<5% by HPLC-MS analysis of re-
action mixture) was observed, and the coupling products
were reliably isolated in good yield. Parallel Suzuki
couplings of simple arylboronic acids to the nonaflates 5
(Table 1, entries 1–4) and 6b (entries 5–8) were also
successful.
F
F
OMe
OH
H
N
N
N
N
NOE
H3C
H
CH3
NOE
4
7b
171 ppm
F3C
O
C
3.33 ppm
Br
N
N
Br
H
132 ppm
H
N
N
NOE
H
H
H3C
12
14d
Figure 1 Selected NMR data used to determine the regiochemistry
of the N-methylpyrazoles.
Table 1 Representative Suzuki Couplings to the Nonaflates 5, 6ba
The complementary routes to the nonaflates 5 and 6b
were applicable to other aryl substituents, but required the
incorporation of the aryl group at the start of the synthesis.
A more versatile, rapid analogue approach12 was sought,
whereby two aryl substituents could be introduced in the
last two steps to a bifunctional N-methylpyrazole with
suitably differentiated reactivity at the two points of
attachment, although only limited examples of such
Entry Ar
Product
7a
Yield (%)b Purity (%)c
1
Ph
56
64
32
53
34
32
10
37
99.3
98.7
99.5
94.5
97.1
94.4
96.6
94.0
2
4-MeO-C6H4
3-NO2-C6H4
2-Me-C6H4
Ph
7b
3
7c
4
7d
5d
6
8a
4-MeO-C6H4
3-NO2-C6H4
2-Me-C6H4
8b
F
7d
8
8c
F
O
O
F
B
8d
F
a General conditions: 1.2 equiv ArB(OH)2, 5 mol% Pd(PPh3)4, 2.4
equiv Na2CO3, DMF, 100 °C, 18 h.
6b
N
F
N
Pd(PPh3)4 (10 mol%)
Na2CO3, DMF, 100 °C
Me
b Unoptimised yields after preparative HPLC purification.
c HPLC AUC (UV detection at 254 nm).
9 (94%)
d 10 mol% Pd(PPh3)4, 2 equiv ArB(OH)2.
Equation 1
Synlett 2004, No. 5, 795–798 © Thieme Stuttgart · New York

LETTER
Rapid Analogue Syntheses of 1-Methyl-3,5-diarylpyrazoles
797
reagents are known.13 The previously unreported 1-meth- Initially, pyrazolone 12 was converted to the correspond-
yl-3-bromopyrazol-5-one (12) was selected as a suitable ing triflate with variable yields [(CF3SO2)2O, pyridine,
synthon, and was prepared on multi-gram scale by adap- CH2Cl2, 0–52%]. Preliminary investigation of room tem-
tation of literature procedures13–16 (Scheme 2). Thus, perature Suzuki couplings to this material indicated
1,1,3,3-tetrabromopropan-2-one (10)14 underwent Favor- chemoselective reaction of the triflate, but the process was
ski rearrangement to 3,3-dibromopropenoic acid15 (67%), compromised by competing cleavage to 12 (30–50% by
which was converted in good yield to the acid chloride 11 HPLC-MS analysis). The nonaflate 13 was more reliably
via formation of the ammonium salt and chlorination with prepared in high yield (90%), and again showed highly
oxalyl chloride16 (87%). The acid chloride 11 was con- chemoselective reaction of the sulfonate group in room
densed with ethyl 3-methylhydrazinecarboxylate17 and temperature Suzuki couplings, accompanied by minimal
cyclised in base13 to give the desired pyrazolone 12. The cleavage to 12 (<10% by HPLC-MS analysis of crude re-
regiochemistry of 12 was identified by the observation of action mixture). The reaction of 13 with arylboronic acids
the non-aromatic pyrazolone tautomer in the CDCl3 1H was conveniently carried out at 40–60 °C to increase the
NMR, and confirmed from the HMBC NMR spectrum by reaction rate, leading to good yields of the bromopyra-
the presence of a 3-bond coupling between the methyl hy- zoles 14 (Table 2, entries 1–5). No reaction of the bromide
drogens and the pyrazolone carbon, and the absence of in 13 was observed under these conditions. Negishi cou-
any coupling between these hydrogens and the bromine- pling of arylzinc halides to 13 at 60–80 °C was similarly
bearing carbon (Figure 1).
chemoselective (entries 6, 7). The regiochemistry of the
bromides 14 was confirmed by the observed NOEs
between the N-methyl group and the aryl substituent (e.g.
14d, Figure 1).
O
O
Br
O
Br
a, b, c
Br
d
Br
N
N
Cl
Br
Br
Br
Me
Ar1
Ar2B(OR)2
Br
Ar1
Ar2
10
11 (59%)
12 (62%)
N
N
N
N
Na2CO3, Pd(PPh3)4
THF-H2O, reflux
Me
Me
e
14a–c
15a–c (41–53%)
Ar1
Br
f or g
Br
C4F9O2SO
Equation 2
N
N
N
N
Me
Me
Table 3 Representative Suzuki Couplings to the Bromides 14
14a–g (41–77%)
13 (90%)
Entry Ar1
Ar2
Prod- Yielda Purity
uct
(%)
(%)b
96.0
99.5
97.9
Scheme 2 Reaction conditions: (a) NaHCO3, H2O, r.t. (67%); (b)
NH3 (g), Et2O, r.t. (96%); (c) (COCl)2, isohexane, reflux (91%); (d) i.
MeNHNHCO2Et, Et3N, CH2Cl2, 0 °C; ii. NaOH, H2O–THF, 60 °C
(62%); (e) NaHMDS, C4F9SO2F, THF, –78 °C to r.t. (f) ArB(OH)2,
Pd(PPh3)4 (10 mol%), Na2CO3, DMF, 40–60 °C; (g) ArZnX,
Pd(PPh3)4 (10 mol%), THF, 60–80 °C.
1c
2d
3d
2-Me-C6H4
3,5-F2-C6H3
15a
44
3-NO2-C6H4
4-MeO-C6H4
4-MeO-C6H4 15b
3-thienyl 15c
41e
53
a Unoptimised yields after preparative HPLC purification.
b HPLC AUC (detection at 254 nm).
c Neopentylglycolatoboronate used.
d Boronic acid used.
Table 2 Chemoselective Couplings to the Nonaflate 13
Entry
Methoda Ar1
Product
14a
Yield (%)b
e Crude yield 90% of material of 82% purity, contaminated with
boronic acid residues.
1
2
3
4
5
6
7
A
A
A
A
A
B
B
2-Me-C6H4
77
51
69
56
59
41
51
3-NO2-C6H4
4-MeO-C6H4
4-CF3-C6H4
14b
14c
A second aryl substituent was installed in the bromides 14
by standard Suzuki coupling at higher temperature
(Equation 2, Table 3).4a As with the nonaflate 6b, incom-
plete conversion (typically 90%) of the starting material
was seen in some of these (unoptimised) reactions. Nev-
ertheless, moderate yields of the products 15, as single
regioisomers, were obtained after purification. The non-
aflate 13 therefore represents a versatile new synthetic
equivalent for the regioselective construction of 3,5-di-
substituted-N-methylpyrazoles.18
14d
14e
3,4-Cl2-C6H3
5-Me-2-pyridyl
3-Cl-4-F-C6H3
14f
14g
a Method A: Ar1B(OH)2, Pd(PPh3)4 (8–10 mol%), Na2CO3, DMF, 40–
60 °C; Method B: Ar1ZnX, Pd(PPh3)4 (10 mol%), THF, 60–80 °C.
b Unoptimised yields of purified products.
In summary, rapid analogue syntheses of 1-methyl-3,5-di-
arylpyrazoles have been developed, based on Pd-catal-
ysed couplings to 1-methyl-3(5)-arylpyrazole nonaflates,
where the nonaflates offered an advantage in hydrolytic
Synlett 2004, No. 5, 795–798 © Thieme Stuttgart · New York

798
S. Bourrain et al.
LETTER
stability over the corresponding triflates. The new bifunc-
tional reagent 1-methyl-3-bromo-pyrazol-5-yl nonaflate
(13) undergoes highly chemoselective Pd-catalysed cou-
pling to the nonaflate functionality, allowing sequential,
regioselective introduction of two aryl substituents in a
short and efficient synthesis.
Acknowledgment
We thank Dr Michael Reader for the preparation of compound 10,
and Kevin Merchant and Dr Linda Keown for helpful discussions.
IC dedicates this paper to his colleagues and friends at MSD.
References
(1) New address: I. Collins, CRUK Centre for Cancer
Therapeutics, The Institute for Cancer Research, 15
Cotswold Road, Sutton, Surrey SM2 5NG, U.K.
Compound 3: MeNHNH2 (1.0 mL) was added to a stirred solution
of 1 (2.75 g) in MeOH (20 mL) at r.t. After 18 h the solvent was re-
duced in volume to ca. 10 mL and the white solid 3 was collected
(1.07 g, 43%). Chromatography of the mother liquors, eluting with
EtOAc–isohexane (2:3 to 4:1), gave further 3 (1.07 g, 41%) and 4
(0.11 g, 4%). 3: 1H NMR (400 MHz, d6-DMSO): d = 3.55 (3 H, s),
5.77 (1 H, s), 7.17 (2 H, dd, J = 9, 9 Hz), 7.72 (2 H, dd, J = 9, 6 Hz),
11.05 (1 H, s). 13C NMR (100 MHz, d6-DMSO): d = 33.1, 83.0,
115.1 (d, J = 22 Hz), 126.3 (d, J = 8 Hz), 130.5, 136.4, 152.8, 161.5
(d, J = 245). MS (ES+): m/z = 193 (M + H)+.
(2) For reviews of the synthesis and biological activity of N-
alkyl pyrazoles see: (a) Elguero, J. Comprehensive
Heterocyclic Chemistry, Vol. 5; Potts, K. T., Ed.; Pergamon:
Oxford, 1984, 167. (b) Elguero, J. Comprehensive
Heterocyclic Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996, 1.
(3) For examples of Pd-catalysed cross-coupling to N-alkyl- or
N-benzyl-3(5)-halopyrazoles see: (a) Tretyakov, E. V.;
Knight, D. W.; Vasilevsky, S. F. J. Chem. Soc., Perkin
Trans. 1 1999, 3713. (b) Paulson, A. S.; Eskildsen, J.;
Vedso, P.; Begtrup, M. J. Org. Chem. 2002, 67, 3904.
(c) Cottineau, B.; Chenault, J. Synlett 2002, 769. (d) Balle,
T.; Andersen, K.; Vedso, P. Synthesis 2002, 1509.
(e) Eskildsen, J.; Ostergaard, N.; Vedso, P.; Begtrup, M.
Tetrahedron 2002, 58, 7635.
(4) For examples of Pd-catalysed cross-coupling to N-aryl-3(5)-
halopyrazoles see: (a) Wang, X.-J.; Tan, J.; Grozinger, K.
Tetrahedron Lett. 2000, 41, 4713. (b) Organ, M. G.; Mayer,
S. J. Comb. Chem. 2003, 5, 118.
(5) Regan, J.; Breitfelder, S.; Crillo, P.; Gilmore, T.; Graham, A.
G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss,
N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.;
Torcellini, C. J. Med. Chem. 2002, 45, 2994.
(6) For a review see: Varvounis, G.; Fiamegos, Y.; Pilidis, G.
Adv. Het. Chem. 2001, 80, 73.
(7) (a) Hamper, B. C.; Kurtzweil, M. L.; Beck, P. J. Org. Chem.
1992, 57, 5680. (b) Sucrow, W.; Slopianka, M.; Vetter, H. J.
Chem. Ber. 1978, 111, 791.
(8) Hendrickson, J. B.; Hussoin, M. S. Synthesis 1989, 217.
(9) Morris, J.; Wishka, D. G. Synthesis 1994, 43.
(10) Rottlander, M.; Knochel, P. J. Org. Chem. 1998, 63, 203.
(11) Renold, P.; Madero, E.; Maetke, T. J. Chromatogr., A 2001,
908, 143.
(12) (a) Collins, I. J. Chem. Soc., Perkin Trans. 1 2000, 2845.
(b) Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921.
(13) Boschi, P. M.; Gozzo, A. L. US Pat. Appl. 4256902, 1981;
Chem. Abstr. 1981, 95, 7281.
Compound 4: H2O (250 mL) and MeNHNH2 (14.6 mL) were add-
ed to a solution of 2 (44.6 g) in EtOH (250 mL). The mixture was
stirred at 60 °C for 7 h, then stood at r.t. for 8 h. The white solid was
collected and rinsed with EtOAc to give the product 4 (29 g, 60%).
1H NMR (400 MHz d6-DMSO): d = 3.60 (3 H, s), 5.62 (1 H, s), 7.31
(2 H, dd, J = 9, 9 Hz), 7.53 (2 H, dd, J = 9, 6 Hz), 9.69 (1 H, s). 13
C
NMR (100 MHz, d6-DMSO): d = 36.5, 90.5, 115.6 (d, J = 21 Hz),
126.8, 130.4 (d, J = 8 Hz), 142.4, 159.8, 161.9 (d, J = 244 Hz). MS
(ES+): m/z = 193 (M + H)+.
1-Methyl-3-bromo-5-pyrazolone (12): A solution of 1116 (13.7 g)
in CH2Cl2 (40 mL) was added dropwise at 0 °C over 20 min to a
stirred solution of ethyl 3-methylhydrazinecarboxylate17 (6.9 g) and
Et3N (8.4 mL) in CH2Cl2 (110 mL). The solution was stirred at 0 °C
under N2 for 2.5 h then washed with H2O (100 mL), dried (Na2SO4)
and concentrated. The yellow oil was dissolved in THF (15 mL) and
added to stirred 1 M NaOH (120 mL) at 60 °C. After 1 h the solution
was cooled, acidified to pH 1 with concd HCl, and extracted with
CH2Cl2 (4 × 100 mL). The extracts were dried (Na2SO4) and con-
centrated. The orange solid was rinsed with boiling Et2O (2 × 20
mL) to give a yellow powder (12, 6.09 g, 62%). 1H NMR (500 MHz,
CDCl3): d = 3.33 (3 H, s), 3.47 (2 H, s). 1H NMR (400 MHz, d6-DM-
SO): d = 3.47 (3 H, s), 5.44 (1 H, s), 11.44 (1 H, s). 13C NMR (d6-
DMSO, 90 MHz): d = 33.6, 88.8, 123.1, 153.5. MS (ES+): m/z =
177, 179 (M + H)+.
Preparation of nonaflates 5, 6b and 13: NaHMDS solution (1.5 M,
THF, 1.2 equiv) was added to a stirred solution of the hydroxypyra-
zole in dry THF (0.3 M) at 0 °C under N2. After 5 min, C4F9SO2F
(1.2 equiv) was added dropwise. The mixture was stirred, warming
slowly to r.t. for 2–4 h, then diluted with 1 M HCl and extracted
with EtOAc. The extracts were dried (Na2SO4) and concentrated.
Chromatography, eluting with EtOAc–isohexane (1:9) gave the
product.
Compound 5: 1H NMR (400 MHz CDCl3): d = 3.86 (3 H, s), 6.39
(1 H, s), 7.09 (2 H, dd, J = 9, 9 Hz), 7.71 (2 H, dd, J = 9, 6 Hz).
19F NMR (376 MHz, CDCl3): d = –126.2, –121.2, –113.7, –108.3,
–81.0. MS (ES+): m/z = 475 (M + H)+.
Compound 6b: 1H NMR (400 MHz, CDCl3): d = 3.81 (3 H, s), 6.15
(1 H, s), 7.20 (2 H, dd, J = 9, 9 Hz), 7.41 (2 H, dd, J = 9, 6 Hz).
19F NMR (376 MHz, CDCl3,): d = –126.3, –121.4, –111.2, –108.9,
–81.1. MS (ES+) m/z = 475 (M + H)+.
Compound 13: 1H NMR (400 MHz, CDCl3,): d = 3.80 (3 H, s), 6.20
(1 H, s). 19F NMR (376 MHz, CDCl3,): d = –126.1, –121.1, –108.0,
–81.2. MS (ES+) m/z = 459, 461 (M + H)+.
(14) (a) Rappe, C. Arkiv Kemi 1964, 21, 503. (b) Kim, H.;
Hoffman, H. M. R. Eur. J. Org. Chem. 2000, 2195.
(15) Rappe, C.; Andersson, K. Arkiv Kemi 1965, 24, 303.
(16) Coates, R. M.; Stack, D. P. Synthesis 1984, 434.
(17) (a) Prepared by a modification of the method described by:
Zinner, G.; Gebhardt, U. Arch. Pharm. 1971, 304, 706.
(b) A solution of MeNHNH2 (26 mL) in (EtO)2CO (60 mL)
was refluxed under N2 for 46 h. The solution was distilled at
1 atm to remove EtOH, then at 10 mmHg through a vigreux
column, collecting the fraction boiling at 60–80 °C.
Chromatography, eluting with MeOH–CH2Cl2 (3:97 then
5:95) gave ethyl 2-methyl-hydrazinecarboxylate (13.5 g,
85% pure by NMR) then ethyl 3-methylhydrazine-
carboxylate (21.3 g, 93% pure by NMR).
(18) Bishop, B. C.; Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J.
Synthesis 2004, 43.
Synlett 2004, No. 5, 795–798 © Thieme Stuttgart · New York