Synthesis of β-tosylethylhydrazine and its use in preparation of N-protected pyrazoles and 5-aminopyrazoles

Article abstract of DOI:10.1016/j.tet.2003.11.046

β-Tosylethylhydrazine (6) can be prepared efficiently in one step from commercially available p-tolyl vinyl sulfone (7) and hydrazine hydrate. This hydrazine reacts with both 1,3-diketones and conjugated ynones in glacial acetic acid to provide a variety of N-tosylethyl-protected (TSE) pyrazoles in good yields. The TSE group can be removed from the pyrazoles using potassium t-butoxide in THF at -30°C-rt. In addition, hydrazine 6 condenses with β-ketonitriles and β-aminoacrylonitriles to afford 5-aminopyrazoles, which can be deprotected by brief treatment with NaOEt in EtOH/DMSO at 45°C.

Full text of DOI:10.1016/j.tet.2003.11.046

Tetrahedron 60 (2004) 901–906
Synthesis of b-tosylethylhydrazine and its use in preparation
of N-protected pyrazoles and 5-aminopyrazoles
b
David M. Dastrup,a Amy H. Yap,a Steven M. Weinreb,a James R. Henry
and Andrew J. Lechleiterb
,
,
*
*
aDepartment of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
bLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 23 October 2003; revised 14 November 2003; accepted 14 November 2003
Abstract—b-Tosylethylhydrazine (6) can be prepared efficiently in one step from commercially available p-tolyl vinyl sulfone (7) and
hydrazine hydrate. This hydrazine reacts with both 1,3-diketones and conjugated ynones in glacial acetic acid to provide a variety of
N-tosylethyl-protected (TSE) pyrazoles in good yields. The TSE group can be removed from the pyrazoles using potassium t-butoxide in
THF at 230 8C–rt. In addition, hydrazine 6 condenses with b-ketonitriles and b-aminoacrylonitriles to afford 5-aminopyrazoles, which can
be deprotected by brief treatment with NaOEt in EtOH/DMSO at 45 8C.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
our synthesis of b-tosylethylhydroxylamine.2c Thus, com-
mercially available bromo acetal 1 reacts with sodium
p-toluenesulfinate to afford sulfone acetal 2 in 54% yield
(Scheme 1).5 Treatment of acetal 2 with ethyl carbazate
under aqueous acidic conditions then leads directly to
acylhydrazone 3 (45%). A more efficient variation of this
route was also developed which involved initial conversion
of bromo acetal 1 to acylhydrazone 4 (65%), which reacts
with sodium p-toluenesulfinate to produce sulfone inter-
mediate 3 in 78% yield. It was then possible to reduce
hydrazone 3 with sodium cyanoborohydride to N-carba-
moylhydrazine 5 in high yield. Unfortunately, despite some
A few years ago we demonstrated that the b-tosylethyl
group (TSE) is useful in N-protection of various types of
amides, carbamates and lactams (including b-lactams), and
can be removed via a b-elimination upon treatment with
potassium t-butoxide in THF under mild conditions.1 This
protecting group can be easily introduced using the readily
prepared reagent b-tosylethylamine.1a,b We subsequently
described the synthesis of b-tosylethylhydroxylamine and
its use in synthesis of TSE-protected g-lactams via our
amidyl radical cyclization methodology.1c In addition, a few
scattered examples have appeared on the use of the TSE and
b-phenylsulfonylethyl groups for N-protection of hetero-
aromatics including tetrazoles,2a pyrroles,2b imidazoles,2c
and indoles.3d In these cases, the protecting groups were
usually installed onto a preformed heterocycle. In the latter
example, the N-protection could also be effected prior to
indole ring construction.2d Once again, TSE removal is
effected in these cases with various bases. In this article we
describe a new extension of our work which involves the
synthesis of b-tosylethylhydrazine (6)3 and its application
to synthesis of TSE-protected pyrazoles and 5-amino-
pyrazoles.4
2. Results and discussion
The initial approach to this hydrazine was patterned after
Keywords: Protecting groups; Nitrogen heterocycles.
*
Corresponding authors. Tel.: þ1-814-8630189; fax: þ1-814-8638403;
e-mail address: smw@chem.psu.edu
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.046

902
D. M. Dastrup et al. / Tetrahedron 60 (2004) 901–906
effort the acyl group of 5 could not be removed
hydrolytically to afford the desired TSE–hydrazine (6).6
Two well known types of condensations were investigated
for construction of the N-TSE-protected pyrazoles.4 In the
first series, TSE-hydrazine (6) was found to combine with
1,3-diketones 8 in glacial acetic acid at room temperature to
generate the pyrazoles 9 in good yields (Scheme 2). Since
this condensation is known to generally produce regio-
isomeric mixtures of pyrazoles with most unsymmetrical
1,3-diketones,4a the reaction was tested with a series of
symmetrical substrates as outlined in Table 1.
We therefore turned to an alternative route for preparation
of the requisite hydrazine 6 which proved to be simpler and
considerably more efficient than the one attempted above.
Thus, by analogy with the work of Hill and Vederas,7
commercially available tosyl vinyl sulfone (7)8 was found to
react smoothly with hydrazine hydrate in methanol at room
temperature for about 15 min to afford 6 in a single step
(Eq. 1).
These pyrazoles can be deprotected by treatment with
potassium t-butoxide in THF starting at 230 8C and
allowing the reaction mixture slowly warm to room
temperature. In general, the yields of deprotected pyrazoles
10 were good, as is shown in Table 1. The vinyl sulfone 7
by-product appears to polymerize under these reaction
conditions.
ð1Þ
Two equivalents of hydrazine hydrate are used here in order
to minimize dialkylation. Hydrazine 6 is rather difficult to
purify but the crude material is sufficiently pure for use
directly in the condensation reactions.
ð2Þ
In addition, conjugated ynones are also known to condense
with hydrazines, often producing pyrazoles regioselectively
depending upon the substrate and reaction conditions.9
It was found that TSE-hydrazine (6) reacts with ynones 11
in glacial HOAc, but the condensations require higher
temperatures (65 8C) than the 1,3-diketones to produce the
pyrazoles 12 (Eq. 2). This pyrazole synthesis has been
explored with a few different ynone systems and the results
are listed in Table 2. In the case of ynone 11a, it was found
that a single regioisomeric pyrazole 12a was formed whose
structure was proven by X-ray crystallography.10 The
Scheme 2.
Table 1. Preparation of TSE-protected pyrazoles from TSE–NHNH2/1,3-diketones, and deprotection with KO–t-Bu/THF
Entry
1,3-Diketone 8
TSE-protected pyrazole 9
Isolated yield (%)
Deprotected pyrazole 10
Isolated yield (%)
a
81
89
b
77
80
c
86
89
71
68
d
e
f
92
69
75
81

D. M. Dastrup et al. / Tetrahedron 60 (2004) 901–906
903
Table 2. Preparation of TSE-protected pyrazoles from TSE–NHNH2 and
ynones
regiochemistry of the protected pyrazole 12b was estab-
lished to be as shown by 1H NMR NOE experiments. With
the ynone in entry d, however, an inseparable 2.2:1 mixture
of regioisomeric pyrazoles was formed.
Entry
Ynone 11
TSE-protected pyrazole 12 Isolated yield (%)
In addition, b-ketonitriles 13 react with hydrazine 6 to
produce 5-aminopyrazoles 15 (Scheme 3). Alternatively,
b-aminoacrylonitriles 14 can also be used in this reaction.
Several substrates were screened in this reaction and the
results are listed in Table 3. For the compounds in entries d
and e, it was best to N-acetylate the crude, highly polar
products with acetyl chloride before chromatographic
purification. The deprotection of these products is sluggish,
perhaps due to additional acidic protons within the
molecules, and does not proceed using the conditions
described above for the pyrazoles. However, if the
deprotection of TSE-substituted aminopyrazole 15b is
conducted with two equivalents of 1 M NaOEt in ethanol
using DMSO as solvent at 45 8C for 30 min, the parent
5-aminopyrazole 16 is produced (Eq. 3).
a
92
b
c
59
62
d
84
ð3Þ
In conclusion, a convenient one-step synthesis of b-tosyl-
ethylhydrazine (6) has been developed from p-tolyl vinyl
sulfone (7). This hydrazine condenses with both b-dike-
tones and alkynyl ketones to directly afford TSE-protected
pyrazoles, often with good regioslectivity in the latter case.
Similarly, TSE-protected 5-aminopyrazoles can be prepared
regioselectively by condensation of 6 with either b-keto-
nitriles or b-aminoacrylonitriles. The N-TSE protecting
Scheme 3.
Table 3. Preparation of TSE-protected 5-aminopyrazoles
Entry
b-Ketonitrile 13 or b-aminoacrylate 14
TSE-protected 5-aminopyrazole 15
Isolated yield (%)
a
58
b
c
50
70
d
88a
e
78a
a
For ease of isolation the condensation product was converted to the N-acetyl derivative before purification.

904
D. M. Dastrup et al. / Tetrahedron 60 (2004) 901–906
group on the heterocycles produced in these reactions can be
removed by exposure to base under mild conditions.
with Et2O. The combined organic fractions were dried
(MgSO4) and concentrated in vacuo. The residue was
purified by flash silica gel chromatography (ethyl acetate/
hexanes, 7/3) to give the hydrazine ethyl ester 5 as a white
1
solid, mp 85–89 8C (1.23 g, 95%). H NMR (360 MHz,
3. Experimental
CDCl3) d 7.82 (d, J¼8.3 Hz, 2H), 7.37 (d, J¼8.0 Hz, 2H),
6.20 (br s, 1H), 4.14 (q, J¼7.1 Hz, 2H), 3.48 (s, 1H), 3.27
(m, 4H), 2.45 (s, 3H), 1.27 (t, J¼7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 157.7, 145.0, 136.2, 130.0, 128.1, 61.6,
54.7, 45.5, 21.7, 14.6; HRMS (C12H18N2O4S) calcd
287.1066 (MHþ), found 287.1065.
3.1. Data for compounds
3.1.1. 1-(2,2-Dimethoxyethyl)-(p-tolyl)sufone (2). To a
solution of sodium p-toluenesulfinate (2.00 g, 11.2 mmol) in
DMF (32 mL) was added bromoacetaldehyde dimethyl
acetal (1, 1.06 mL, 9.35 mmol). The resulting solution was
stirred overnight at 100 8C, cooled to rt, and diluted with
ether (30 mL). The ether layer was washed with brine, dried
over MgSO4 and concentrated in vacuo to afford the known
tosyl acetal 26 as pale yellow solid (1.33 g, 60%). 1H NMR
(400 MHz, CDCl3) d 7.77 (dd, J¼6.6, 1.7 Hz, 2H), 7.34 (d,
J¼7.9 Hz, 2H), 4.85 (t, J¼5.3 Hz, 1H), 3.40 (d, J¼5.3 Hz,
2H), 3.23 (s, 6H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 144.9, 137.1, 129.8, 128.4, 99.3, 59.0, 53.6, 21.8.
3.1.5. [2-(p-Tosyl)-ethyl]-hydrazine (6). To a rapidly
stirred solution of hydrazine monohydrate (107 mL,
2.20 mmol) in methanol (4 mL) was added dropwise a
solution of p-tolyl vinyl sulfone (7) (200 mg, 1.10 mmol) in
methanol (4 mL). After stirring for 15 min at rt, the solution
was diluted with H2O and extracted with CH2Cl2. The
combined organic fractions were dried (MgSO4) and
concentrated in vacuo. The resulting thick colorless oil
was used immediately without further purification
(204 mg, 87%). 1H NMR (360 MHz, CDCl3) d 7.76
(d, J¼8.3 Hz, 2H), 7.34 (d, J¼8.3 Hz, 2H), 3.36 (s, 3H),
3.30 (m, 2H), 3.11 (m, 2H), 2.41 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 143.3, 136.6, 130.3, 128.5, 54.4, 47.9,
22.0; HRMS (C9H14N2O2S) calcd 215.0842 (MHþ), found
215.0848.
3.1.2. N0-(2-Bromoethylidene)-hydrazinecarboxylic acid
ethyl ester (4). To a solution of ethyl carbazate (9.01 g,
86.6 mmol) in aqueous HCl (1 M, 300 mL) was added
bromoacetaldehyde dimethyl acetal (1, 5.00 mL,
43.3 mmol). The solution was stirred overnight, and was
extracted with CH2Cl2. The extract was dried with MgSO4,
and concentrated in vacuo to afford the bromide 4 as a white
1
3.2. General procedure for the formation of TSE-
protected pyrazoles 9 from 1,3-diketones 8
solid (5.87 g, 65%). H NMR (400 MHz, CDCl3) (mixture
of geometric isomers) d 8.05 (br s, 1H), 7.24 (br s, 1H),
4.28 (m, 2H), 4.21 (d, J¼5.8 Hz, 1.2H), 4.08 (d, J¼6.2 Hz,
0.8H), 1.30 (m, 3H); HRMS (C5H9BrN2O2) calcd 208.9926
(MHþ), found 208.9914.
A solution of TSE–NHNH2 (6, 154 mg, 0.719 mmol) and
1,3-diketone 8 (0.497 mmol) in glacial acetic acid (4 mL)
was stirred at rt for 16 h. The solution was concentrated in
vacuo and the residue was purified by flash silica gel
chromatography (ethyl acetate/hexanes, 3/7) to give the
corresponding TSE-protected pyrazole 9 (Table 1).
3.1.3. N0-[2-(p-Tosyl)-ethylidene]-hydrazinecarboxylic
acid ethyl ester (3). Sodium p-toluenesulfinate (7.45 g,
41.8 mmol) was added in one portion to the bromide 4
(5.83 g, 27.9 mmol) in CH2Cl2–H2O (1:1, 100 mL). The
mixture was stirred rapidly at rt overnight, diluted with H2O,
and extracted with CH2Cl2. The extract was dried (MgSO4)
and concentrated in vacuo to give the hydrazone 3 as a light
yellow solid (6.18 g, 78%).
3.2.1. 3,5-Diphenyl-1-[2-(p-tosyl)-ethyl]-1H-pyrazole
(9a/12c). Gummy yellow foam (82% yield). 1H NMR
(400 MHz, CDCl3) d 7.69–7.17 (m, 14H), 6.48 (s, 1H), 4.51
(m, 2H), 3.78 (m, 2H), 2.27 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 151.3, 145.4, 145.0, 136.0, 133.0, 130.0, 129.1,
128.9, 128.7, 128.4, 128.0, 127.9, 125.6, 103.8, 55.4, 43.5,
21.6; HRMS (C24H22N2O2S) calcd 403.1480 (MHþ), found
403.1468.
1H NMR (300 MHz, CDCl3) (mixture of geometric isomers)
d 8.35 (br s, 1H), 7.74 (m, 2H), 7.33 (m, 3H), 4.24 (m, 2H),
4.09 (m, 2H), 2.44 (m, 3H), 1.27 (m, 3H).
3.2.2. 3,5-Diphenyl-1-[2-(p-tosyl)-ethyl]-1H-pyrazole
1
(9b). White solid (77% yield); mp 76–79 8C; H NMR
Alternatively, a solution of sulfone 2 (2.40 g, 10.1 mmol)
and ethyl carbazate (3.15 g, 104.1 mmol) in aqueous HCl
(1 M, 60 mL) was heated for 6 h at 100 8C. After the
solution was cooled the precipitated hydrazone was
removed by filtration as a light yellow solid (1.30 g, 45%).
(400 MHz, CDCl3) d 7.71–7.6 (m, 2H), 7.31–7.28 (m, 2H),
5.72 (s, 1H), 4.38–4.34 (m, 2H), 3.72–3.67 (m, 2H), 2.98–
2.87 (m, 1H), 2.81–2.70 (m, 1H), 2.41 (s, 3H), 1.22–1.20
(m, 6H), 1.13–1.11 (m, 6H); 13C NMR (75 MHz, CDCl3) d
159.3, 150.4, 145.3, 136.6, 130.3, 128.5, 99.0, 56.2, 42.2,
28.3, 25.6, 23.1, 22.1; HRMS (C18H26N2O2S) calcd
335.1788 (MHþ), found 335.1770.
3.1.4. N0-[2-(p-Tosyl)-ethyl]-hydrazinecarboxylic acid
ethyl ester (5). To a solution of hydrazone 3 (1.29 g,
4.54 mmol) and a trace of methyl orange in methanol
(17 mL) at 0 8C was added sodium cyanoborohydride
(570 mg, 9.08 mmol). The pH was adjusted periodically to
the red–yellow transition point (pH 3.2–4.4) by addition of
25% HCl in methanol (prepared from acetyl chloride/
MeOH). The reaction was followed by TLC (ethyl acetate/
hexanes, 7/3), until the hydrazone was consumed (,1 h).
The solution was basified with 1 M NaOH and extracted
3.2.3. 3,5-Diethyl-1-[2-(p-tosyl)-ethyl]-1H-pyrazole (9c).
Yellow oil (86% yield). 1H NMR (360 MHz, CDCl3) d 7.69
(m, 2H), 7.29 (m, 2H), 5.72 (s, 1H), 4.33 (m, 2H), 3.65 (m,
2H), 2.56 (m, 2H), 2.44 (m, 5H), 1.22 (t, J¼7.5 Hz, 3H),
1.11 (t, J¼7.6 Hz, 3H); 13C NMR (90 MHz, CDCl3) d
154.6, 145.6, 145.0, 136.4, 130.0, 127.9, 102.0, 55.8, 42.0,

D. M. Dastrup et al. / Tetrahedron 60 (2004) 901–906
905
21.8, 21.5, 18.8, 13.9, 12.9; HRMS (C16H22N2O2S) calcd
307.1475 (MHþ), found 307.1487.
3.4.2. 5-Ethyl-3-methyl-1-[2-(p-tosyl)-ethyl]-1H-pyra-
1
zole (12b). Yellow oil (59% yield). H NMR (400 MHz,
CDCl3) d 7.67 (m, 2H), 7.30 (m, 2H), 5.69 (s, 1H), 4.31 (m,
2H), 3.64 (m, 2H), 2.56 (q, J¼7.5 Hz, 2H), 2.42 (s, 3H),
2.06 (s, 3H), 1.21 (t, J¼7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 148.7, 145.9, 145.2, 136.4, 130.2, 128.2, 103.9,
55.6, 42.1, 22.0, 19.0, 13.8, 13.1; HRMS (C15H20N2O2S)
calcd 293.1318 (MHþ), found 293.1295.
3.2.4. 3,5-Dimethyl-1-[2-(p-tosyl)-ethyl]-1H-pyrazole
1
(9d). White solid (89% yield). Mp 65–67 8C; H NMR
(300 MHz, CDCl3) d 7.68 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼
8.4 Hz, 2H), 5.68 (s, 1H), 4.33 (m, 2H), 3.65 (m, 2H), 2.42
(s, 3H), 2.23 (s, 3H), 2.05 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 148.3, 144.9, 139.4, 136.2, 129.9, 127.8, 105.4,
55.6, 41.9, 21.7, 13.4, 10.9; HRMS (C14H18N2O2S) calcd
279.1167 (MHþ), found 279.1141.
3.4.3. 5-Butyl-3-phenyl-1-[2-(p-tosyl)-ethyl]-1H-pyrazole
and 3-butyl-5-phenyl-1-[2-(p-tosyl)-ethyl]-1H-pyrazole
(12, entry d). Yellow oil (84% yield), 2.2:1 inseparable
1
3.2.5. 4-Butyl-3,5-dimethyl-1-[2-(p-tosyl)-ethyl]-1H-pyr-
azole (9e). Pale yellow solid (92% yield); mp 81–84 8C;
1H NMR (300 MHz, CDCl3) d 7.67 (d, J¼8.3 Hz, 2H), 7.28
(d, J¼8.3 Hz, 2H), 4.33 (m, 2H), 3.65 (m, 2H), 2.42 (s, 3H),
2.22 (t, J¼7.1 Hz, 2H), 2.14 (s, 3H), 2.00 (s, 3H), 1.33–1.26
(m, 4H), 0.90 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 146.9, 144.8, 136.2, 136.1, 129.8, 127.8, 117.0,
55.6, 42.1, 33.1, 23.2, 22.5, 21.7, 14.1, 11.8, 9.5; HRMS
(C18H26N2O2S) calcd 335.1793 (MHþ), found 335.1770.
mixture of regioisomers. H NMR (300 MHz, CDCl3) d
7.57–7.18 (m, 37H), 6.11 (s, 1H), 5.93 (s, 2.3H), 4.33 (m,
6.6H), 3.63 (m, 2.4H), 3.57 (m, 4.7H), 3.00 (m, 1.4H), 2.43
(m, 15.9H), 2.18 (s, 3.6H), 1.3 (m, 17.9H), 0.87 (m, 11H);
13C NMR (75 MHz, CDCl3) d 153.7, 151.0, 145.0, 144.9,
144.7, 136.1, 135.9, 133.4, 130.3, 130.0, 129.9, 129.1,
128.9, 128.8, 128.6, 128.3, 128.0, 127.7, 127.6, 125.5,
105.4, 101.8, 55.6, 50.8, 43.0, 42.4, 31.8, 30.7, 28.0, 25.2,
22.7, 22.5, 21.8, 21.6, 14.1, 14.0; HRMS (C22H26N2O2S)
calcd 383.1788 (MHþ), found 383.1783.
3.2.6. 4-Chloro-3,5-dimethyl-1-[2-(p-tosyl)-ethyl]-1H-
1
pyrazole (9f). White solid (69% yield); mp 80–82 8C; H
3.5. General procedure for formation of TSE-protected
5-aminopyrazoles from b-ketonitriles or b-amino-
acrylonitriles
NMR (400 MHz, CDCl3) d 7.63–7.61 (d, J¼8.1 Hz, 2H),
7.29–7.27 (d, J¼8.1 Hz, 2H), 4.35–4.31 (m, 2H), 3.71–
3.67 (m, 2H), 2.43 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 145.2, 144.9, 135.9, 129.7, 127.6,
107.9, 55.1, 43.0, 21.7, 11.2, 9.3; HRMS (C14H17N2O2SCl)
calcd 313.0757 (MHþ), found 313.0772.
A solution of TSE–NHNH2 (6, 154 mg, 0.719 mmol) and
the b-ketonitrile or b-aminoacrylonitrile (0.497 mmol) in
glacial acetic acid (4 mL) was stirred at 65 8C for 14 h. The
solution was concentrated in vacuo and the residue was
purified by flash silica gel chromatography to give the
corresponding TSE-protected 5-aminopyrazole.
3.3. General procedure for deprotection of
TSE-protected pyrazoles
To a solution of a TSE protected pyrazole 9 (0.107 mmol) in
THF (5 mL) at 230 8C was added t-BuOK (428 mL, 1 M
in THF). The solution was warmed slowly to rt, and stirred
for an additional 1 h. The mixture was diluted with H2O
and extracted with EtOAc. The combined organic fractions
were dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash silica gel chromatography (ethyl
acetate/hexanes, 2/3) to give the deprotected pyrazole 10
(Table 1).
3.5.1. 5-tert-Butyl-2-[2-(p-tosyl)-ethyl]-2H-pyrazol-3-yl-
1
amine (15a). 58%. H NMR (400 MHz, CDCl3) d 7.61 (d,
J¼8.3 Hz, 2H), 7.25 (d, J¼7.9 Hz, 2H), 5.28 (s, 1H), 4.33 (t,
J¼6.2 Hz, 2H), 3.77 (s, 2H), 3.68 (t, J¼6.4 Hz, 2H), 2.40 (s,
3H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3) d 161.5,
144.9, 144.6, 136.4, 129.8, 127.4, 88.4, 55.7, 40.6, 32.2,
30.4, 21.8; HRMS (C16H23N3O2S) calcd 322.1589 (MHþ),
found 322.1564.
3.5.2. 5-Phenyl-2-[2-(p-tosyl)-ethyl]-2H-pyrazol-3-yl-
amine (15b). 50%. 1H NMR, (400 MHz, d6-DMSO) d
7.75 (d, J¼8.3 Hz, 2H), 7.54 (dd, J¼8.1, 1.5 Hz, 2H), 7.36
(d, J¼7.9 Hz, 2H), 7.28 (d, J¼7.9 Hz, 2H), 7.20 (t, J¼
7.3 Hz, 1H), 5.64 (s, 1H), 5.25 (s, 2H), 4.18 (t, J¼7.0 Hz,
2H), 3.77 (m, 2H), 2.32 (s, 3H); 13C NMR (100 MHz,
d6-DMSO) d 148.5, 144.9, 136.5, 134.4, 130.3, 128.7,
128.1, 127.5, 125.2, 86.6, 54.2, 41.2, 21.5; HRMS
(C18H19N3O2S) calcd 342.1198 (MHþ), found 342.1257.
3.4. General procedure for the formation of
TSE-protected pyrazoles 12 from ynones 11
A solution of TSE–NHNH2 (6, 154 mg, 0.719 mmol) and
ynone 11 (0.497 mmol) in glacial acetic acid (4 mL) was
stirred at 65 8C for 14 h. The solution was concentrated in
vacuo and the residue was purified by flash silica gel
chromatography (ethyl acetate/hexanes, 3/7) to give the
corresponding TSE-protected pyrazole 12 (Table 2).
3.5.3. 5-Methyl-4-phenyl-2-[2-(p-tosyl)-ethyl]-2H-pyra-
1
zol-3-ylamine (15c). 70%. H NMR, (400 MHz, CDCl3) d
3.4.1. 5-Phenyl-3-methyl-1-[2-(p-tosyl)-ethyl]-1H-pyra-
zole (12a). White solid, mp 89–92 8C (92% yield). A
sample for X-ray analysis was crystallized from CH2Cl2/
hexanes. 1H NMR (300 MHz, CDCl3) d 7.57–7.18 (m, 9H),
5.92 (s, 1H), 4.33 (m, 2H), 3.58 (m, 2H), 2.35 (s, 3H), 2.10
(s, 3H); 13C NMR (75 MHz, CDCl3) d 148.8, 145.0, 144.9,
136.0, 130.2, 130.0, 129.1, 128.9, 128.8, 128.1, 106.5, 55.6,
43.1, 21.8, 13.6; HRMS (C19H20N2O2S) calcd 341.1318
(MHþ), found 341.1319.
7.63 (d, J¼8.3 Hz, 2H), 7.39 (t, J¼7.5 Hz, 2H), 7.26–7.17
(m, 5H), 4.37 (t, J¼6.4 Hz, 2H), 3.96 (s, 2H), 3.72 (t, J¼
6.2 Hz, 2H), 2.40 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 146.0, 144.6, 142.5, 136.1, 133.3, 129.7, 128.8,
128.4, 127.4, 125.9, 105.3, 55.3, 40.9, 21.8, 13.0; HRMS
(C19H21N3O2S) calcd 356.1432 (MHþ), found 356.1444.
The following compounds were isolated as acetamides to

906
D. M. Dastrup et al. / Tetrahedron 60 (2004) 901–906
simplify purification. After heating for 14 h, the crude
reaction mixtures were cooled to rt and 4 equiv. of acetyl
chloride were added to the acetic acid solution. After 1 h,
the reactions were worked up as above to give the title
compounds.
References and notes
1. (a) DiPietro, D.; Borzilleri, R. M.; Weinreb, S. M. J. Org.
Chem. 1994, 59, 5856. (b) Borzilleri, R. M.; Weinreb, S. M.;
Parvez, M. J. Am. Chem. Soc. 1995, 117, 10905. (c) Artman,
G. D., III; Waldman, J. H.; Weinreb, S. M. Synthesis 2002,
2057 and references cited.
3.5.4. N-{5-Methyl-2-[2-(p-tosyl)-ethyl]-2H-pyrazol-3-
1
yl}-acetamide (15d). 88%. H NMR, (400 MHz, CDCl3)
2. (a) Faubl, H. Tetrahedron Lett. 1979, 491. (b) Gonzalez, C.;
Greenhouse, R.; Tallabs, R.; Muchowski, J. M. Can. J. Chem.
1983, 61, 1697. (c) Rao, A. K. S. B.; Rao, C. G.; Singh, B. B.
Synth. Commun. 1994, 24, 341. (d) Bashford, K. E.; Cooper,
A. L.; Kane, P. D.; Moody, C. J. Tetrahedron Lett. 2002, 43,
135.
d 8.18 (s, 1H), 7.63 (d, J¼7.9 Hz, 2H), 7.30 (d, J¼7.9 Hz,
2H), 6.02 (s, 1H), 4.38 (t, J¼6.4 Hz, 2H), 3.62 (t, J¼6.2 Hz,
2H), 2.43 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 168.7, 148.7, 145.1, 136.1, 135.8,
129.9, 127.5, 100.1, 55.8, 41.1, 23.7, 21.8, 14.1; HRMS
(C15H19N3O3S) calcd 322.1225 (MHþ), found 322.1207.
3. Hydrazine 6 has only been reported previously as a minor
by-product of a reaction: Kloosterziel, H.; Backer, H. J. Recl.
Trav. Chim. Pays-Bas 1952, 71, 361.
3.5.5. N-{5-(2-Pyridyl)-2-[2-(p-tosyl)-ethyl]-2H-pyrazol-
1
3-yl}-acetamide (15e). 78%. H NMR, (400 MHz, CDCl3)
4. For reviews of pyrazoles see: (a) Kost, A. N.; Grandberg, I. I.
Adv. Heterocycl. Chem. 1966, 6, 347. (b) Elguero, J.
Comprehensive heterocyclic chemistry II; Shinkai, I., Ed.;
Elsevier: Oxford, 1996; Vol. 3, p 3. (c) Makino, K.; Kim, H. S.;
Kurasawa, Y. J. Heterocycl. Chem. 1998, 35, 489. (d) Makino,
K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1999, 36,
321. (e) Stanovnik, B.; Svete, J. Science of synthesis,
Houben-Weyl methods of molecular transformations; Neier,
R., Ed.; Thieme: Stuttgart, 2002; Vol. 12, p 15.
d 8.73 (s, 1H), 8.56 (d, J¼4.8 Hz, 1H), 7.67–7.61 (m, 4H),
7.24–7.15 (m, 3H), 6.74 (s, 1H), 4.47 (t, J¼6.6 Hz, 2H),
3.72 (t, J¼6.6 Hz, 2H), 2.28 (s, 3H), 2.17 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 169.2, 151.4, 150.6, 149.1, 145.1,
137.1, 136.5, 135.6, 129.9, 127.5, 122.6, 120.2, 99.1, 55.5,
41.9, 23.5, 21.7; HRMS (C19H20N4O3S) calcd 385.1334
(MHþ), found 385.1322.
3.6. Deprotection of 5-phenyl-2-[2-(p-tosyl)-ethyl]-2H-
pyrazol-3-ylamine (15b)
5. Compound 2 has been previously prepared from the
corresponding chloro acetal: Field, L.; Holsten, J. R.; Clark,
R. D. J. Am. Chem. Soc. 1959, 81, 2572.
5-Phenyl-2-[2-(p-tosyl)-ethyl]-2H-pyrazol-3-ylamine (15b,
62 mg, 0.18 mmol) was dissolved in 5 mL of DMSO and
0.45 mL of a 1.0 M solution of NaOEt in EtOH was added at
rt. The mixture was then heated at 45 8C for 30 min, cooled
to rt, and quenched with 0.45 mL of 1.0 N aqueous HCl. The
solvent was removed in vacuo, and the residue was
subjected to silica gel flash chromatography (9:1 EtOAc/
MeOH) to yield 17 mg (60%) of the known 5-phenyl-2H-
pyrazol-3-ylamine (16).
6. (a) For a review of alkyl hydrazine synthesis see: Ragnarsson,
U. Chem. Soc. Rev. 2001, 30, 205. (b) Cf. Corey, E. J.; Gross,
A. W. J. Org. Chem. 1985, 50, 5391.
7. Hill, R. D.; Vederas, J. C. J. Org. Chem. 1999, 64, 9538.
8. Vinyl sulfone 7 can also be prepared from b-tosylethanol: Lee,
J. W.; Lee, C. W.; Jung, J. H.; Oh, D. Y. Synth. Commun. 2000,
30, 2897.
9. See for example: (a) Falorni, M.; Lardicci, L.; Giacomelli, G.
Gazz. Chim. Ital. 1987, 117, 7. (b) Miller, R. D.; Reiser, O.
J. Heterocycl. Chem. 1993, 30, 755. (c) Ananchenko, G. S.;
Petrov, A. A.; Ershov, B. A. Russ. J. Org. Chem. 1999, 35,
153. (d) Cuadrado, P.; Gonzalez-Nogal, A. M.; Valero, R.
Tetrahedron 2002, 58, 4975.
Acknowledgements
The work at Penn State was supported by a research grant
from the National Institutes of Health (CA-34303), and
by NSF grant CHE-0131112 for purchase of an X-ray
diffractometer. We thank Dr. Hemant Yennawar (Penn State
Small Molecule X-ray Crystallographic Facility) for
determining the structure of compound 12a.
10. X-ray data has been deposited with the Cambridge Crystallo-
graphic Data Centre (CCDC 222360).