Propargyl hydrazides: Synthesis and conversion into pyrazoles through hydroamination

Article abstract of DOI:10.1002/chem.201202828

Pyrazoles direct: Propargyl alcohols undergo hydrazination when treated with p-tosyl hydrazide in the presence of catalytic amounts of either Sc(OTf)₃ or La(OTf)₃ (see scheme; Tf= trifluoromethanesulfonyl). Propargyl hydrazides are converted into either N-tosyl or N-H pyrazoles when treated with an acid or a base, respectively. The one-step acid-catalyzed hydrazination/cyclization of propargyl alcohols directly affords pyrazoles in high yields. Copyright

Full text of DOI:10.1002/chem.201202828

DOI: 10.1002/chem.201202828
Propargyl Hydrazides: Synthesis and Conversion Into Pyrazoles Through
Hydroamination
Mitsuhiro Yoshimatsu,* Katsuki Ohta, and Nami Takahashi[a]
À
Direct C N bond forming reactions of propargyl alcohols
have received considerable attention because the products,
propargyl amines and their derivatives, can be converted
into a wide variety of heterocycles through either one-pot or
stepwise cyclizations. In particular, propargyl hydrazides
have been converted into heterocycles that contain either
one or two nitrogen atoms, compounds that exhibit various
biological activities.[1] Similarly, alkenyl and propargyl
amines and their derivatives can be readily accessed from
the corresponding halides,[2] alcohols,[3] esters,[4] and imines[5]
using novel methodologies based on metal-catalyzed and
metal-free aminations; such transformations can also be car-
ried out in an enantioselective manner.[6] However, methods
for preparing alkenyl and propargyl hydrazides are very lim-
ited. In particular, propargyl hydrazides are useful inter-
mediates in Mannich-type coupling reactions of aldehydes
with hydrazines to generate pyrazoles,[7] which have diverse
biological activities, including antihyperglycemic, analgesic,
anti-inflammatory, antipyretic, and antibacterial activities.[8]
To the best of our knowledge, while there are a few prepara-
tive methods for the hydrohydrazination of enynes[9] and the
allylation of hydrazones,[10] direct hydrazination of alcohols
has not yet been reported.[11] We recently achieved direct
Table 1. Direct hydrazination of propargyl alcohols.
Entry R1
R2
R3
T/t
2 (Yield [%])[a]
1
2
3
4
5
6
7
Ph
H
H
H
H
H
H
H
Ph
Ph
Ph
458C, 5 h
508C, 1 h
508C, 1 h
2a (84)
2b (67)
2c (78)
p-FC6H4
1-naphthyl
Ph
2-thienyl
p-MeOC6H4
2-thienyl
nBu reflux, 7 min 2d (68)
nBu RT, 1.5 h
PhS RT, 50 min
PhS RT, 1.5 h
2e (96)
2 f (90)
2g (86)
8
H
PhS 508C, 13 min 2h (65)
PhS 508C, 40 min 2i (98)
9
1-napthyl
H
H
H
10
PhS RT, 1 h
2j (98)
11
12
13
14
15
16
p-FC6H4
PhS 608C, 0.5 h
PhS 508C, 1.5 h
PhS 508C, 3 h
2k (91)
2l (75)
2m (66)
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
PhS 508C, 15 min 2n (68)
n-pentyl PhS RT, 3.5 h 2o (64)
p-FC6H4 PhS reflux, 5 min 2p (56)
n-pentyl
p-FC6H4
À
À
Lewis acid catalyzed C C and C O bond formation of
propargyl alcohols with nucleophiles in MeNO2/H2O, a reac-
tion medium that provided high regioselectivity and chemo-
selectivity.[12] We therefore decided to study the more chal-
lenging direct hydrazination of propargyl alcohols and a sub-
sequent intramolecular hydroamination that is tunable with
either the addition of an acid or a base.
[a] Yield of isolated product. Tf=trifluoromethanesulfonyl, Ts=p-tolu-
enesulfonyl.
AHCTUNGTRENNUNG
(0.10 equivalents), Bu4NHSO4 (0.10 equivalents), MeNO2/
H2O (10:1), either 308C or reflux for 5—15 minutes. Propar-
gyl alcohols containing a sulfur substituent on the alkyne
ACHTUNGTRENNUNG
First, we screened nitrogen nucleophiles in the direct
Lewis acid catalyzed hydrazination of propargyl alcohols in
MeNO2/H2O and were pleased to find that the reactions
with p-tosylhydrazine proceeded to afford the desired pro-
ACHTUNGTRENNUNG
moiety are highly reactive toward hydrazination and afford
the propargyl hydrazides even at room temperature. Howev-
er, alcohols bearing either nBu or Ph R3 substituents did not
react at room temperature, although the hydrazination of
these less reactive substrates can be readily achieved under
reflux conditions. Hydrazination of phenylsulfanyl cycloal-
kanols 1l–1n also provided the corresponding products in
satisfactory yields. Dialkyl- and diaryl-propargyl alcohols
provided the desired products in moderate yields (Table 1,
entries 15 and 16). The structures of the products were con-
firmed using deuteration experiments. When deuterium
oxide was added to the NMR sample of 2c, the resulting
1H NMR spectrum no longer showed the characteristic two
peaks at d 4.77 and 6.19 ppm, signals that correspond to the
NH protons of the hydrazine moiety. All the other spectral
ACHTUNGTRENNUNGparACHTUNGTRENNUNGgyl hydrazines (Table 1). The typical reaction conditions
À
À
developed in our research group for other C C and C O
bond forming reactions with alcohols were applied to the
À
C N bond formation with hydrazines: scandium triflate
[a] Prof. Dr. M. Yoshimatsu, K. Ohta, N. Takahashi
Department of Chemistry, Faculty of Education
Gifu University, Yanagido 1-1, Gifu 501-1193 (Japan)
Fax : (+81)58-293-2251
E-mail: yoshimae@gifu-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202828.
15602
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Chem. Eur. J. 2012, 18, 15602 – 15606

COMMUNICATION
Table 3. AuCl/AgClO4-catalyzed cyclization of propargyl hydrazides.
data supported the assignment of the structures as being the
indicated propargyl hydrazides. Next, intramolecular cycliza-
tion of the propargyl hydrazides using either acid or base
was investigated, because in comparison with propargyl-
ACHTUNGTRENNUNGamines, propargyl hydrazides are less utilized as precursors
to useful heterocycles.[13] First, the acid-catalyzed cyclization
of propargyl hydrazides was investigated (Table 2).
Using the optimized reaction conditions for the acid-cata-
lyzed cyclization of propargyl hydrazides, the scope of the
AuCl/AgClO4 catalyzed cyclization was evaluated. The reac-
Entry
R1
R2
t (h)
3 (Yield [%])
1
2
3
4
5
6
p-FC6H4
1-naphthyl
Ph
2-thienyl
p-MeOC6H4
2-thienyl
Ph
Ph
nBu
nBu
PhS
PhS
8
10
3
1.5
1.5
2.5
3b (97)
3c (97)
3d (79)
3e (70)
3 f (98)
3g (91)
Table 2. Screening of acid-catalyzed cyclization of 2a.
7
PhS
2
3h (61)
8
9
10
1-napthyl
2,4,6-Me3C6H2
p-FC6H4
PhS
PhS
PhS
3.5
2.5
4
3i (95)
3j (90)
3k (98)
Entry
Reaction conditions
Yield
Yield
3a [%]
2a [%]
1
2
3
4
5
6
7
8
9
AgClO4 (10 mol%), CH2Cl2, RT, 1.2 h
CuOTf (10 mol%), CH2Cl2, RT, 1.5 h
CuI (10 mol%), CH2Cl2, RT, 1.2 h
62
40
47
24
4
Yb
ACHTUNGTRENNUNG(OTf)3 (10 mol%), CH2Cl2, reflux, 3 h
La(OTf)3 (10 mol%), CH2Cl2, reflux, 3 h
ACHTUNGTRENNUNG
AuCl (10 mol%), DCE, reflux, 5 min
AgClO4 (10 mol%), MeNO2, reflux, 3.5 h
AuCl (20 mol%), CH2Cl2, RT, 45 min
AuCl (2 mol%), TBAC (10 mol%)
CH2Cl2/H2O, reflux, 2 h
36
84
72
67
Scheme 1. AuCl/AgClO4-catalyzed transformation of 1-ethynyl-1-hydra-
zinocycloalkanes.
N
ACHTUNGTRENNUNG
10
11
12
13
AgClO4 (2 mol%), TBAB (10 mol%)
CH2Cl2/H2O, RT, 2 h
58
96
66
91
AuCl (5 mol%), AgClO4 (15 mol%)
TBAS (20 mol%), CH2Cl2/H2O, reflux, 2 h
AuCl (5 mol%), AgSbF6 (15 mol%)
TBAS (20 mol%), CH2Cl2/H2O, reflux, 3 h
AuCl (2.5 mol%), AgClO4 (20 mol%)
TBAS (20 mol%), CH2Cl2/H2O, reflux, 7 h
2
16
TBAB=tetra-n-butylammonium bromide, TBAC=tetra-n-butylammoni-
um chloride, TBAS=tetra-n-butylammonium hydrogen sulfate.
tions of hydrazides with R1 substituents, pFC6H4 and 1-naph-
thyl, gave pyrazoles 3b and 3c, respectively (Table 3, en-
tries 1 and 2). The use of hydrazides bearing a n-butyl group
instead of a phenyl group as the R2 substituent gave good
yields of the corresponding products (Table 3, entries 3 and
4). Similarly, the reactions of phenylsulfanyl hydrazides pro-
ceeded to completion faster than the hydrazides bearing n-
butyl and phenyl groups in and gave the corresponding ex-
cellent yields (Table 3, entries 5—10). Furthermore, the cy-
Scheme 2. Proposed reaction mechanism.
hydrazide 6, which leads to a gold-substituted pyrazoline in-
termediate 7 through an intramolecular 5-endo-dig cycliza-
tion. The elimination of both tosylate and hydrogen chloride
from 7 generates gold(I)-stabilized intermediate 8.[14] The
1,2-hydride shift of intermediate 8 gives the benzyl cation 9,
which could release the gold(I) catalyst with concomitant
formation of product 3. To determine if a different mecha-
nism is operating, the desulfonylation of 10 to give 3 f was
attempted under the same reaction conditions that were
used for the intramolecular cyclization (Scheme 3). This re-
action did not proceed at all at room temperature; however,
under reflux for 8 hours, the desired 3 f was obtained in
56% yield, accompanied by the tosylhydrazide 10 (44%).
ACHTUNGTRENNUNGcliACHTUNGTRENNUNGzation of ethynylcycloalkylhydrazides was investigated
using the AuCl/AgClO4 reaction conditions (Scheme 1). The
yield of pyrazoles decreases as the size of the cycloalkyl
groups increases (5- to a 7-membered ring), the side prod-
ucts being b-elimination products, that is, ethynylcycloal-
kenes.
On the basis of the above results and our previous studies,
a plausible reaction mechanism for the intramolecular cycli-
zation of the propargyl hydrazides is outlined in Scheme 2.
First, gold activates the acetylenic group of the propargyl
Chem. Eur. J. 2012, 18, 15602 – 15606
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M. Yoshimatsu et al.
Table 5. Direct synthesis of pyrazoles from propargyl alcohols.
Entry
1
R1
Ph
R2
Ph
Reaction conditions
Sc(OTf)3 (10 mol%)
Product
(Yield [%])
Scheme 3. Attempted desulfonylation of tosyl pyrazoles.
AHCTUNGTRENNUNG
N
3a (90)
The difficulty in achieving the desulfonylation reaction
under acidic conditions suggests that 10 is not an intermedi-
ate in the catalytic cycle and that elimination of the tosyl
group occurs in the manner in which it is depicted in
Scheme 2.
AgClO4 (20 mol%)
MeNO2, RT, 5 h
ScACTHNGUTREN(NUG OTf)3 (10 mol%)
AgClO4 (20 mol%)
AuCl (5 mol%)
508C, 20 min
2
Ph
nBu
3d (67)
In addition to the AuCl/AgClO4-catalyzed reaction, the
base-promoted cyclization of propargyl hydrazides was also
investigated (Table 4). Surprisingly, when using either
3
4
p-MeOC6H4
PhS
PhS
Sc
(OTf)3 (5 mol%)
3 f (83)
3g (74)
AuCl (5 mol%)
408C, 2 h[a]
2-thienyl
ScACTHNGUTREN(NUG OTf)3 (5 mol%)
AuCl (5 mol%)
reflux, 5 min[a]
Table 4. Base-promoted cyclization of propargyl hydrazides.
ScACTHUNTRGENNG(U OTf)3 (5 mol%)
5
PhS
AuCl (5 mol%)
3h (82)
508C, 45 min[a]
6
7
1-naphthyl
PhS
PhS
AuCl (10 mol%)
508C, 5 h[a]
3i (63)
3k (57)
Entry
R1
R2
Reaction conditions
Product
(Yield [%])
p-FC6H4
AuCl (10 mol%)
608C, 3 h[a]
AHCTUNGTRENNUNG
1
2
3
4
5
6
Ph
Ph
Cs2CO3 (1.2 equiv)
acetone, RT, 4.5 h
Cs2CO3 (1.2 equiv)
acetone, RT, 3 h
LDA (2 equiv)
THF, RT, 4 h
tBuOK (3 equiv)
tBuOH, reflux, 3.5 h
NaH (1 equiv)
THF, 08C, 2 h
Cs2CO3 (1.2 equiv)
acetone
LDA (2 equiv)
THF, RT, 20 min
10a (88)
10e (42)
10 f (55)
3 f (69)
[a] MeNO2/H2O (10:1), Bu4NHSO4 (20 mol%).
2-thienyl
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-FC6H4
nBu
PhS
PhS
PhS
PhS
Finally, the transformation of sulfanyl pyrazoles was dem-
onstrated using previously reported methods (Scheme 4).
1,3,5-Triarylsubstituted pyrazoles have been used in halo-
genation–arylation protocols with arylboronic acids (Suzuki
coupling process) to give 1,3,4-triarylpyrazoles.[15] Halogena-
tion of the NH pyrazoles using either N-chlorosuccinimide
(NCS) or N-bromosuccinimide (NBS) readily afforded the
chlorinated derivative 11a and the brominated derivative
11b, respectively; however, the subsequent palladium-cata-
lyzed arylation of the NH halopyrazoles with arylboronic
10 f (60)
3 f (15)
10h (43)
7
PhS
10i (49)
LDA=lithium diisopropylamine.
cesium carbonate or LDA, N-tosylpyrazoles were obtained
as the sole product, instead of 1H-pyrazoles. On the other
hand, when sodium alkoxides were used, such as sodium
methoxide and tBuOK in the appropriate alcoholic solvent,
the desulfonylated pyrazole 3 f, which was obtained using
the acid-catalyzed cyclization of the propargyl hydrazides,
was obtained. The use of sodium hydride in THF gave a
mixture of 10 f and 3 f (Table 4, entry 5).
Next, the direct synthesis of pyrazoles from propargyl al-
cohols was attempted (Table 5). Notably, the use of 5 mol%
AuCl provided the pyrazoles 3 f and 3h. A combination of
scandium triflate and gold chloride was also efficient for this
procedure (Table 5, entries 3, 6, and 7). Therefore, this
metal-catalyzed tandem hydrazination–desulfonylation–cyc-
lization process represents a one-step synthesis of pyrACHTUNTRGNEUNGazoles
from propargyl alcohols with p-tosyl hydrazine.
Scheme 4. Transformations of sulfanyl pyrazoles.
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Chem. Eur. J. 2012, 18, 15602 – 15606

Propargyl Hydrazides
COMMUNICATION
acids did not proceed to give the 3,4-diarylpyrazoles.[7e,16]
Next, N-methylation and arylation were attempted using the
same procedure. On the other hand, the N-tosylpyrazoles
underwent arylation and desulfonylation to afford 13a via 4-
iodopyrazole 12 in excellent yields. The cross-coupling of
heteroaryl halides is extensively used for preparing pharma-
ceutical intermediates; however, these procedures suffer
from deactivation of the metal catalysts because of the bind-
ing of these metals with heteroatom moieties, such as NH,
OH, CO2H, SH, and NH2. To overcome the problem of cat-
alyst deactivation, many researchers have resorted to either
incorporating additional protection and deprotection steps
of N-aryl and N-alkyl derivatives prior to and after the cou-
pling reaction, or seeking more effective ligands and cata-
tive TLC on silica gel eluting with CHCl3 to give spirocyclohexane-5-
(phenylsulfanyl)-3H-pyrazole (4m; 71 mg, 58%) as a pale yellow oil.
Typical procedure for the direct hydrazination/cyclization of propargyl al-
cohols: To a nitromethane/H2O (10:1, 1.1 mL) solution of 1-thienyl-3-
(phenylsulfanyl)propargyl alcohol (1g) (50 mg, 0.20 mmol), p-toluenesul-
fonyl hydrazide (45 mg, 0.24 mmol), and tetrabutylammonium hydrogen-
sulfate (14 mg, 0.04 mmol) at room temperature were added scandium
triflate (14 mg, 0.04 mmol) and gold(I) chloride (2.4 mg, 0.01 mmol). The
reaction mixture was stirred for 5 min at reflux and then poured into
water (50 mL). Workup as detailed in the procedure above for the prepa-
ration of 4m was followed to give 3g (39 mg, 74%).
À
Keywords: C N bond formation
heterocycles · hydrazides · hydroamination · propargylic
amines · pyrazoles
· cycloisomerization ·
lysts. The novel scandium-catalyzed hydrazination of pro
ACHTUNGTNERpNUNG ar-
ACHTUNGTRENNUNG
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stituted or tosyl-free products provides an alternative route
to pyrazoles with significant potential applications. For ex-
ample, sulfonylated 3,4-bisACHTNUTRGNE(UNG aryl)pyrazoles, are known to un-
dergo desulfanylation when treated with Raney Ni to afford
the polyarylpyrazoles.[15]
In conclusion, we report the first convenient method for
the preparation of propargyl hydrazides from the corre-
sponding alcohols through scandium-catalyzed hydrazina-
tion in MeNO2/H2O. Moreover, gold/silver-catalyzed reac-
tions and base-promoted cyclizations of the hydrazides lead
to the formation of N-tosyl pyrazoles and N-H pyrazoles, re-
spectively. Furthermore, both gold and a combination of
scandium and gold catalysts facilitate the one-step transfor-
mation of propargyl alcohols into pyrazoles. Therefore, this
protocol provides access to a wide variety of aryl-substituted
pyrazoles through either stepwise or one-step protocols.
Experimental Section
Typical procedure for preparation of propargyl hydrazides: To a nitro-
ACHTUNGTRENNUNGmethACHTUNGTRENNUNGane/H2O (10:1, 22 mL) solution of 1,3-diphenyl-2-propyn-1-ol (1a;
1.0 g, 4.8 mmol), p-toluenesulfonyl hydrazide (2.7 g, 14.5 mmol), and tet-
rabutylammonium hydrogensulfate (0.16 g, 0.48 mmol) at room tempera-
ture was added scandium triflate (0.24 g, 0.48 mmol). The reaction mix-
ture was stirred for 10 h at 408C and then poured into saturated aqueous
sodium hydrogen carbonate (100 mL). The organic layer was separated
and the aqueous layer was extracted with AcOEt. The organic layer and
the extracts were combined and dried over MgSO4. The solvent was re-
moved under reduced pressure. The residue was purified by column chro-
matography on silica gel eluting with CHCl3/n-hexane (5:1) to give 1-(p-
tosylhydrazino)-3-phenyl-2-propyn-1-ylbenzene (2a; 1.38 g, 76%) as a
white powder. M.p. 140–1428C.
Typical procedure for the AuCl/AgClO4-catalyzed cyclization leading to
3,5-disubstituted pyrazoles: To a dichloromethane/H2O (10:1, 15.4 mL)
solution of 1-(phenylsulfanylethynyl)-1-(p-toluenesulfonylhydrazino)cy-
clohexane (2m; 0.20 g, 0.50 mmol) and tetrabutylammonium hydrogen-
sulfate (17 mg, 0.05 mmol) were added silver perchlorate (21 mg,
0.10 mmol) and then gold(I) chloride (5.8 mg, 0.0025 mmol). The reaction
mixture was stirred at reflux for 2 h. The cooled mixture was poured into
a saturated aqueous sodium hydrogencarbonate (50 mL). The organic
layer was separated and the aqueous layer was extracted with CHCl3.
The combined organic layers were dried over MgSO4. The solvent was
removed under reduced pressure. The residue was purified by prepara-
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Received: August 7, 2012
Revised: October 5, 2012
Published online: November 9, 2012
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