Pyrazole synthesis using a titanium-catalyzed multicomponent coupling reaction and synthesis of withasomnine

Article abstract of DOI:10.1002/adsc.200900293

The titanium-catalyzed 3-component coupling of an alkyne, isonitrile, and amine can be used to generate tautomers of 1,3-diimines. These diimines produced in situ undergo cyclization with hydrazine and hydrazine derivatives in a one-pot procedure to provi

Full text of DOI:10.1002/adsc.200900293

FULL PAPERS
DOI: 10.1002/adsc.200900293
Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent
Coupling Reaction and Synthesis of Withasomnine
Supriyo Majumder,a Kevin R. Gipson,a Richard J. Staples,a and Aaron L. Odoma,*
a
Michigan State University, Department of Chemistry, East Lansing, MI 48824, USA
Fax : (+1)-517-353-1793; e-mail: odom@chemistry.msu.edu
Received: April 24, 2009; Published online: August 5, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900293.
Abstract: The titanium-catalyzed 3-component cou- regioselectivity of monosubsituted hydrazines to un-
pling of an alkyne, isonitrile, and amine can be used symmetrical 1,3-diimines is discussed. This multicom-
to generate tautomers of 1,3-diimines. These di- ponent coupling strategy was applied to the synthesis
ACHTUNGTRENNUNGimines produced in situ undergo cyclization with hy- of withasomnine in an efficient procedure, which
drazine and hydrazine derivatives in a one-pot proce- gave the natural product in 24% overall yield from
dure to provide pyrazoles. Seventeen examples of 4-pentyn-1-ol.
pyrazoles are provided using this one-pot, 4-compo-
nent procedure from simple starting materials. The
regioselectivity of the alkyne addition can be con- Keywords: heterocycles; hydrazines; multicompo-
trolled in some cases with catalyst architecture, and nent reactions; pyrazoles; titanium
Introduction
alyzed 3-component coupling[4] of an alkyne, isoni-
trile, and primary amine to generate unsymmetrical
Catalyzed multicomponent coupling reactions offer 1,3-diimine tautomers.[5] Pyrazoles result from simply
the opportunity to generate important classes of mol- removing the volatiles from the multicomponent cou-
ecules, such as heterocycles, in a small number of pling reaction and treating the crude product with
steps. The main advantages of this type of scheme are commercially available hydrazines.[6] Finally, we pres-
the time the researcher saves in the preparation of ent a new, concise synthesis of the natural product
the compounds, the variety of compounds that can be withasomnine using this multicomponent coupling
made using these protocols by varying substituents in methodology.
the starting materials, and the availability of catalyst
tuning to provide regio-, stereo-, or even chemoselec-
tive control from one set of substrates.[1]
Results and Discussion
Pyrazoles and related structures are important het-
erocycles for their applications to pharmaceuticals The multicomponent coupling reaction utilized here is
such as celecoxib (Celebrexꢀ), sildenafil (Viagraꢀ), a formal alkyne iminoamination, addition of iminyl
and rimonabant (Acompliaꢀ); they are also one of and amino groups across the triple bond.[4,7] The pro-
the most common cores found in herbicides, fungi- posed mechanism for the reaction is shown in
cides, and insecticides.[2] Pyrazoles are also found in a Scheme 1. Titanium was added as the dimethylamido-
few natural products such as withasomnine. Witha- containing precatalysts, which are easily synthesized
somnine is a popular compound in alternative medi- from commercially available TiACHTUNGTRNEUNG
(NMe2)4.[8] The dime-
cine found in several plant species with alleged appli- thylamido ligands are protolytically removed by the
cations to a variety of ailments. It has been shown to primary amine substrate[9] to generate titanium imido
be a mild analgesic and a central nervous system de- complexes that undergo [2+2]cycloaddition with al-
pressant.[3]
kynes.[10] The resulting azatitanacyclobutenes undergo
In this study, we demonstrate that a variety of dif- 1,1-insertion of isonitriles to generate 5-membered
ferent pyrazoles can be prepared in a one-pot, 4-com- metallacycles.[11] The 5-membered metallacycles are
ponent fashion. The methodology uses a titanium-cat- protolytically converted back to imides by primary
Adv. Synth. Catal. 2009, 351, 2013 – 2023
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2013

Supriyo Majumder et al.
FULL PAPERS
Scheme 1. Proposed mechanism for titanium-catalyzed imi-
noamination of alkynes with the overall reaction shown.
amines with concomitant release of the iminoamina-
tion products.
For this study, we employed two different pyrrole-
based catalysts. Both catalysts use ligand architectures
synthesized in a single step from pyrrole, and both an-
cillary ligands can be placed on titanium in near
quantitative yields by reaction with commercially
Scheme 2. Synthesis of H2dpma, H2dpm, Ti
(1), and Ti(NMe2)2A(dpm) (2).
ACHUTGTNERN(NUG NMe2)2ACHTUNGTRENNUNG(dpma)
G
CHTUNGTRENNUNG
available Ti
scribed for this 3-component coupling reaction was
Ti(NMe2)2A
(dpma),[12] where dpma[13] =N,N-di(pyrrol-
yl-a-methyl)-N-methylamine. More recently, we have coupling procedure, and catalyst variations can be
found that Ti(NMe2)2A
(dpm),[14] where dpm[15] =5,5-di- used to control regioselectivity giving different prod-
pyrrolylmethane, is a quite active catalyst for alkyne ucts from the same substrates. We explored the reac-
iminoamination. tions of in situ generated iminoamination products
ACHTUNGTRENNUNG(NMe2)4 (Scheme 2). The first catalyst de-
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
The multicomponent coupling reaction can be with hydrazines in the presence of base. The reactions
facile using both terminal and internal alkynes with a can be carried out with an isolated iminoamination
variety of amines. Because the substituent on the iso- product, or more conveniently, in a one-pot procedure
nitrile does not end up in the final pyrazole product, generating the pyrazoles directly from alkyne, amine,
tert-butyl isonitrile was employed exclusively here be- isonitrile, and hydrazine (Scheme 3).
cause of its general applicability in this reaction. Ease
The general procedure involved the addition of
of access is also an advantage for t-BuNC, which is amine (1 mmol), catalyst (10 mol%), alkyne
both commercially available and readily prepared (1 mmol), isonitrile (1–1.5 mmol), and 2 mL of tolu-
from tert-butylamine and chloroform in the presence ene to a 40-mL pressure tube under nitrogen, which
of base.[16]
was sealed and heated at 1008C with stirring. Once
Barluenga and co-workers published a large series the multicomponent coupling reaction was complete
of notable papers in “1-azabutadiene” chemistry as judged by GC-FID, the volatiles were removed
where the intermediates were obtained by reaction of under vacuum and 3 mL of pyridine along with hydra-
saturated nitriles with Schiff bases using AlCl3.[17] zine or hydrazine hydrochloride were added to the
These 1-azabutadienes are close derivatives of the crude residue. After additional heating,[18] the product
iminoamination products used here; however, the pyrazole (3) was purified by chromatography or crys-
available substitution patterns are quite different. In tallization.
addition, the iminoamination procedure produces
Some applications of the methodology are shown in
these useful intermediates in a one-step, 3-component Table 1 and Table 2. For this initial study, we chose to
2014
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2013 – 2023

Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent Coupling Reaction
FULL PAPERS
Table 1. Examples of pyrazole (3) syntheses using phenyl-
AHCTUNGTRENNaGUN cetylene and a variety of hydrazines.
Entry Hydrazine Product GC or NMR
3
G
Yield[a]
a
PhN(H)NH2
57 (48)
b
NH2NH2·H2O
51 (43)
52 (45)
Scheme 3. One-pot synthesis of pyrazoles (3).
c
C6H11N(H)NH2
look at the multicomponent coupling product of phe-
nylacetylene, tert-butyl isonitrile, and cyclohexylamine
with a variety of different hydrazines, which generat-
ed pyrazoles 3a–i. All the hydrazines attempted
seemed about equally successful in the second step of
the reaction, and a large variety of N-substituted and
d
t-BuN(H)NH2
68 (50)
À
N H pyrazoles can likely be prepared in comparable
yields.
e
f
MeN(H)NH2
BnN(H)NH2
(35)
In the second stage of the study (Table 2), a selec-
tion of different internal and terminal alkynes was
used with phenylhydrazine, which generated pyrazoles
3j–q. Terminal alkynes and 1-phenylpropyne reactions
could be done with the milder catalyst 1. More diffi-
cult substrates like diphenylacetylene and 3-hexyne
required 2 as catalyst, sometimes with increased cata-
lyst loadings or longer reaction times.
In one case (3j), the product was structurally char-
acterized by X-ray diffraction to help ensure proper
assignment of the regiochemistry as the 1,4,5-trisubsti-
tuted pyrazole. See the Supporting Information for
details.
Not only do the two catalysts differ in their reactiv-
ity, but the regioselectivity of reactions with 1 and 2
was often different as well. In general, dipyrrolylme-
thane 2 favored 4-substitution in the pyrazole prod-
ucts when terminal alkynes were employed. The tri-
dentate ligand 1 favored 4-substitution for aromatic
groups and 3-substitution (or 5-substitution – vide
infra) for alkyl-containing alkynes.
For example, reactions with 1-hexyne as substrate
and catalysts 1 and 2 were carried out under similar
conditions (Scheme 4).[19] Catalyst 1 provides 3-butyl-
pyrazole (3r) as the major isomer, while catalyst 2
generates 4-butylpyrazole (3s) as the major prod-
uct.[20]
45 (45)
g
4-MeOC6H4-N(H)NH2
4-CNC6H4-N(H)NH2
60 (45)
53 (41)
46 (39)
h
4-CO2MeC6H4-
N(H)NH2
i
[a]
10 mol% 1 used as catalyst.
If an alkyl- or arylhydrazine is employed with an
unsymmetrical 3-component coupling product, mix- For example, the 3-component coupling product[4] de-
tures could potentially result due to different re- rived from 1-phenylpropyne reacts with phenylhydra-
gioisomers from the hydrazine addition [Eq. (1)]. zine to give 1-phenyl-4-phenyl-5-methylpyrazole (3j)
Even so, one isomer can often be strongly favored. with 9:1 selectivity over the alternative isomer 1-
Adv. Synth. Catal. 2009, 351, 2013 – 2023
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2015

Supriyo Majumder et al.
FULL PAPERS
Table 2. Examples of pyrazole (3) syntheses using phenyl-
ACHTUNGTRENNUNGhydrazine with other alkynes.
As might be expected, several of the compounds in
Table 1 have been prepared previously. In general,
the route here often compares favorably with previ-
ously reported syntheses in number of steps, overall
yield, or both. For example, one can examine 4-phe-
nylpyrazole (3b), which we prepare in 43% yield in a
single step from phenylacetylene. In this case, the
product precipitates from the reaction mixture and is
collected by filtration and recrystallized. There are
several distinct routes to the same compound.[22] For
example, Vilsmeier formylation of phenylacetalde-
hyde diethyl acetal followed by hydrazine affords 4-
phenylpyrazole in 36% yield in two steps.[23] The pyra-
zole was prepared in 8% yield by Suzuki coupling of
5-B(OH)2-pyrazole and PhCl.[24] Kumada coupling of
1-trityl-4-bromopyrazole and PhMgBr catalyzed by
Entry Alkyne
Product (3)
GC or NMR
(Isolated) Yield
AHCTUNGTRENNUNG
j
45 (40)[a,d]
39 (37)[b]
34 (24)[c]
k
l
PdCl2ACTHNURGTNE(NUG dppf) is high yielding but requires 4 steps from
pyrazole.[25]
We also applied this methodology to the synthesis
of the natural product withasomnine, which has been
prepared using a diverse array of routes.[26] The ad-
vantages of the multicomponent coupling strategy
presented here are the inexpensive and readily avail-
able reagents used in a straightforward synthesis
(Scheme 5) of the natural product.
High yielding Sonogoshira coupling of iodobenzene
and 4-pentyn-1-ol followed by protection of the alco-
hol by tert-butylACTHNUTRGNEUNG(dimethyl)silation provided alkyne
m
50 (41)[a]
n
o
35 (28)[b]
(31)[b]
4.[27] Iminoamination using 10 mol% 2, aniline, and
tert-butyl isonitrile followed by addition of hydrazine
hydrate gave pyrazole 5 with the desired regioselec-
tivity. The TBDMS protection was removed and con-
verted to the alkyl bromide with BBr3. Some of the
natural product 6 was formed during the reaction
with tribromoborane, and ring-closure was completed
with the addition of NaOEt/HOEt to provide witha-
somnine in 71% yield from 5. The overall yield was
24% from the 4-pentyn-1-ol. This is comparable in
yield to the recently reported synthesis by Allin
et al.,[28] which used 4-bromopyrazole as the starting
material with an interesting radical cyclization to
close the aliphatic ring.
p
q
45 (38)[b]
44 (35)[a]
[a]
10 mol% 1.
10 mol% 2.
20 mol% 2.
[b]
[c]
[d]
See Eq. (1) and text for regioselectivity discussion.
Conclusions
phenyl-3-methyl-4-phenylpyrazole[21] [Eq. (1)]. Meth- Titanium-catalyzed 3-component coupling of primary
ods for controlling the regioselectivity further in this amine, alkyne, and isonitrile followed by treatment
step are under investigation.
with hydrazines provides pyrazoles in a one-pot pro-
cedure. This new procedure has significant flexibility
in the types of pyrazoles that can be accessed. The
yields are generally modest, but the products are
readily isolated using either column chromatography
or crystallization. Reactions with terminal alkynes are
more facile and can be accomplished with the milder
TiACHTUNRTGENNUG(dpma)ACHTUNGTRNE(NUGN NMe2)2 (1) as catalyst. The more active di-
2016
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2013 – 2023

Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent Coupling Reaction
FULL PAPERS
Scheme 4. Regioselectivity of pyrazole formation using 1-hexyne as the substrate and catalyst 1 and 2.
Experimental Section
General Considerations
All manipulations of air-sensitive compounds were carried
out in an MBraun dry box under a purified nitrogen atmos-
phere. Toluene was purified by purging with dry N2, then
water was removed by running through activated alumina
systems purchased from Solv-Tek. Deuterated solvents were
dried over purple sodium benzophenone ketyl (C6D6) or
phosphoric anhydride (CDCl3) and distilled under a nitro-
gen atmosphere. Deuterated toluene was degassed then
dried by passing through two columns of neutral alumina.
1H and 13C NMR spectra were recorded on VXR-500 spec-
trometers. Melting points were measured on a Mel-Temp II
apparatus with a mercury thermometer and are uncalibrat-
(NMe2)2 (2)[14] and Ti (NMe2)2 (1)[12] were
ed. TiACHTUNGRETN(UNNG dpm)ACHTUNGTERNNUG AHCTUNGERTNNG(UN dpma)ACTHNUGTRENNUGN
Scheme 5. Synthesis of withasomnine (6). (i) 1 mol%
Pd(PPh3)4, 2 mol% CuI, 2 equiv. PhI, 10 equiv. NEt3, THF.
(ii) ClSiMe2A(t-Bu), imidazole, DMF. (iii) PhNH2, t-BuNC,
10 mol% 2, 1108C, 48 h, toluene. (iv) NH2NH2, pyridine,
1508C, 24 h. (v) BBr3, CH2Cl2, room temperature, 48 h. (vi)
NaOEt, HOEt, reflux, 20 h.
made following the literature procedures. Alkynes were pur-
chased either from Sigma–Aldrich Co. or from GFS chemi-
cals and dried from CaO under dry nitrogen. Amines were
purchased from Sigma–Aldrich Co., dried over KOH, and
distilled under dry nitrogen. tert-Butyl isonitrile[16] was made
from CHCl3 and tert-butylamine according to the reported
procedure and purified by distillation under nitrogen. Phe-
nylhydrazine was purchased from Sigma–Aldrich Co. and
distilled from KOH. Hydrazine hydrate was purchased from
Spectrum Chemicals and used as received. All other hydra-
zines were purchased from Sigma–Aldrich Co. as hydrochlo-
ride salts and used as received. Pyridine was dried over
KOH and distilled under nitrogen. The alkynes 5-(tert-butyl-
dimethylsilyloxy)-1-phenylpent-1-yne and 5-phenylpent-4-
yn-1-ol were made according to the literature procedures.[27]
The GC yields in Table 1 are from crude reaction mixtures
relative to internal octane added after reaction completion
and are calibrated versus pure product/octane standards.
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
pyrrolylmethane catalyst Ti
used for internal alkynes.
ACHUTGTNRNE(NUG dpm)CAHTUNGTREN(NUGN NMe2)2 (2) was
The reaction has several points to allow optimiza-
tion for a specific target of interest. For example, the
type of substituent on the isonitrile can potentially be
varied in this reaction to improve regioselectivities or
yields. The catalyst architectures themselves are also
quite flexible and could be optimized for specific
products. In fact, it was found that some regiochemi-
cal control is possible using simple catalysts 1 and 2
with alkyl-substituted terminal alkynes, and either 3-
butyl- or 4-butylpyrazole can be synthesized from the
same substrates preferentially depending on the cata-
lyst employed (Scheme 4).
General Procedure for the Synthesis of Pyrazoles 3
In an N2-filled glove box, a 40-mL pressure tube equipped
with a magnetic stirbar was loaded with amine (1 mmol),
catalyst (10–20 mol%), alkyne (1 mmol), isonitrile (1–
1.5 mmol), and dry toluene (2 mL). The pressure tube was
sealed with a Teflon screw cap, taken out of the dry box,
and heated to the appropriate temperature for the desired
time with vigorous stirring. After completion of the reaction,
The 3-component coupling followed by hydrazine
treatment strategy was also applied to the synthesis of
the natural product withasomnine (6) from commer-
cially available 4-pentyn-1-ol in 24% overall yield.
Adv. Synth. Catal. 2009, 351, 2013 – 2023
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2017

Supriyo Majumder et al.
FULL PAPERS
the pressure tube was cooled to room temperature, and vol-
atiles were removed under reduced pressure. Then the tube
was charged with hydrazine or hydrazine hydrochloride
(1.5 mmol) in pyridine (3 mL) and heated to 1508C for 24 h.
After completion of the reaction, volatiles were removed
under reduced pressure. The crude product was dissolved in
CH2Cl2 and washed with water. The organic layer was dried
over Na2SO4 and concentrated on a rotary evaporator. The
crude product was purified either by column chromatogra-
phy or by crystallization from a suitable solvent.
(2H, m, cyclohexyl), 2.17–2.2 (2H, m, cyclohexyl), 4.08–4.14
(1H, m, 1-cyclohexyl), 7.17–7.20 (1H, m, Ar-H), 7.31–7.34
(2H, m, Ar-H), 7.44–7.46 (2H, m, Ar-H), 7.64 (1H, d, J=
0.5 Hz, 3-CH-pyrazole), 7.75 (1H, d, J=0.5 Hz, 5-CH-pyra-
zole); 13C{1H} NMR (CDCl3, 125 MHz): d=25.4, 33.6, 61.4,
122.3, 123.5, 125.4, 126.2, 128.8, 132.9, 136.0. Two of the res-
onances, assigned as being due to the 3- and 4-carbons of
the cyclohexyl, are coincident in the 13C NMR spectrum at
25.39 ppm. MS (EI): m/z=226 (M+); high resolution MS:
+
m/z=227.1552, calcd. for C15H19N2 : 227.1548.
1,4-Diphenylpyrazole (3a): A reaction using the general
conditions was carried out with tert-butyl isonitrile (171 mL,
1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phenylacety-
1-tert-Butyl-4-phenylpyrazole (3d): A reaction using the
general conditions was carried out with tert-butyl isonitrile
(171 mL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phe-
lene (102 mg, 1 mmol), and Ti
G
G
nylacetylene (102 mg, 1 mmol), and TiACHTUGNTRENNU(G NMe2)2ACHTUNGTRNE(NUNG dpma) (1,
0.1 mmol) in toluene (2 mL) and was heated for 24 h at
1008C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was hexanes:ethyl acetate 9:1, which afforded
the desired compound as a pale yellow solid; yield: 106 mg
(48%); mp 95–968C (Lit.[29] mp: 978C). 1H NMR (CDCl3,
500 MHz): d=7.28–7.34 (2H, m, Ar-H), 7.42 (2H, t, J=
7.5 Hz, Ar-H), 7.49 (2H, t, J=8 Hz, Ar-H), 7.57–7.59 (2H,
m, Ar-H), 7.75–7.77 (2H, m, Ar-H), 8.03 (1H, d, J=0.5 Hz,
3-CH-pyrazole), 8.17 (1H, d, J=1 Hz, 5-CH-pyrazole);
13C{1H} NMR (CDCl3, 125 MHz): d=119.0, 123.3, 124.9,
125.7, 126.5, 126.8, 128.9, 129.4, 132.0, 138.8, 140.0; MS (EI):
m/z=220 (M+); high resolution MS: m/z=211.1065, calcd.
32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for
24 h at 1008C. Volatiles were removed, and tert-butylhydra-
zine hydrochloride (187 mg, 1.5 mmol) in dry pyridine
(3 mL) was added. The mixture was heated to 1508C for
24 h. Purification was accomplished by column chromatogra-
phy on neutral alumina. The eluent was hexanes:ethyl ace-
tate 9:1, which afforded the desired compound as a yellow
liquid; yield: 100 mg (50%) 1H NMR (CDCl3, 500 MHz):
d=1.61 (9H, s, CH3), 7.18 (1H, tt, J=7.5 and 1 Hz, 4-H-
Ph), 7.33 (2H, t, J=8 Hz, Ar-H), 7.46–7.48 (2H, m, Ar-H),
7.74 (1H, d, J=1 Hz, 3-CH-pyrazole), 7.78 (1H, s, 5-CH-
pyrazole); 13C{1H} NMR (CDCl3, 125 MHz): d=29.8, 58.5,
122.2, 122.6, 125.4, 126.1, 128.8, 133.0, 136.1; MS (EI): m/z=
200 (M+); high resolution MS: m/z=201.1393, calcd. for
+
C13H17N2 : 201.1392.
+
for C15H13N2 : 221.1079.
1-Methyl-4-phenylpyrazole (3e): A reaction using the gen-
eral conditions was carried out with tert-butyl isonitrile
(855 mL, 7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phe-
4-Phenylpyrazole (3b): A reaction using the general con-
ditions was carried out with tert-butyl isonitrile (855 mL,
7.5 mmol), cyclohexylamine (495 mg, 5 mmol), phenylacety-
nylacetylene (510 mg, 5 mmol), and TiACHTUNTRGENNUG(NMe2)2ACHTUNGTRENNUNG(dpma)
lene (510 mg, 5 mmol), and Ti
(NMe2)
E
(323 mg, 1 mmol) in toluene (10 mL) and was heated for
24 h at 1008C. Volatiles were removed, and methylhydrazine
(345 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The
mixture was heated to 1408C for 24 h. After completion of
the reaction, pyridine was removed under reduced pressure
and crude product was dissolved in EtOAc and washed with
water. The organic layer was dried over Na2SO4 and concen-
trated on a rotary evaporator. The crude product was puri-
fied by column chromatography using 20% ethyl acetate/
hexanes on neutral alumina; yield: 280 mg (35%); mp 98–
0.5 mmol) in toluene (10 mL) and was heated for 24 h at
1008C. Volatiles were removed, and hydrazine hydrate
(375 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The
mixture was heated to 1508C for 24 h. Pyridine was re-
moved under vacuum, and the crude product was recrystal-
lized from methanol/ethyl acetate to afford the desired
product as a white solid; yield: 310 mg (43%); mp 233–
2348C (Lit.[23] mp: 235–2368C). 1H NMR (DMSO-d6,
500 MHz): d=7.15 (1H, t, J=7.5 Hz, Ar-H), 7.32 (2H, t, J=
7.5 Hz, Ar-H), 7.57 (2H, dd, J=7.5 and 1.5 Hz, Ar-H), 7.89
(1H, br s, 3-CH pyrazole), 8.15 (1H, br s, 5-CH pyrazole),
12.90 (1H, br s, NH); 13C{1H} NMR (DMSO-d6, 125 MHz):
d=121.1, 125.1, 125.3, 125.8, 128.7, 132.9, 136.1; MS (EI):
m/z=144 (M+).
1
998C (Lit.[30] mp: 100–1018C). H NMR (CDCl3, 500 MHz):
d=3.92 (3H, s, CH3), 7.20 (1H, tt, J=7.5 and 1 Hz, Ar-H),
7.34 (2H, t, J=8 Hz, Ar-H), 7.44–7.46 (2H, m, Ar-H), 7.58
(1H, s, 3-CH-pyrazole), 7.74 (1H, d, J=0.5 Hz, 5-CH-pyra-
zole); 13C{1H} NMR (CDCl3, 125 MHz): d=39.1, 123.2,
125.5, 126.3, 126.8, 128.8, 132.6, 136.7; MS (EI): m/z=158
(M+); high resolution MS: m/z=159.0909, calcd. for
1-Cyclohexyl-4-phenylpyrazole (3c): A reaction using the
general conditions was carried out with tert-butyl isonitrile
(171 mL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phe-
+
C10H11N2 : 159.0922.
nylacetylene (102 mg, 1 mmol), and Ti
G
E
1-Benzyl-4-phenylpyrazole (3f): A reaction using the gen-
eral conditions was carried out with tert-butyl isonitrile
(171 mL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), phe-
32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for
24 h at 1008C. Volatiles were removed, and cyclohexylhy-
drazine hydrochloride (226 mg, 1.5 mmol) in dry pyridine
(3 mL) was added. The mixture was heated to 1508C for
24 h. Purification was accomplished by column chromatogra-
phy on neutral alumina. The eluent was hexanes:ethyl ace-
tate 9:1, which afforded the desired compound as a yellow
solid; yield: 102 mg (45%); mp 69–708C. H NMR (CDCl3,
500 MHz): d=1.22–1.30 (1H, m, cyclohexyl), 1.38–1.48 (2H,
m, cyclohexyl), 1.70–1.78 (3H, m, cyclohexyl), 1.88–1.91
nylacetylene (102 mg, 1 mmol), and TiACHTNUGTRENNUG(NMe2)2ACHTUNGTRNE(NUGN dpma) (1,
32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for
24 h at 1008C. Volatiles were removed, and benzylhydrazine
(183 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was 15% ethyl acetate/hexanes, which afforded
the desired compound as a white solid; yield: 105 mg
2018
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2013 – 2023

Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent Coupling Reaction
FULL PAPERS
1
(45%); mp 92–948C (Lit.[31] mp: 95–968C). 1H NMR
(CDCl3, 500 MHz): d=5.35 (2H, s, N-CH2), 7.25 (1H, t, J=
7.5 Hz, Ar-H), 7.27–7.29 (2H, d, J=8 Hz, Ar-H), 7.35–7.40
(5H, m, Ar-H), 7.50 (2H, dd, J=8.5 and 1 Hz, Ar-H), 7.64
(1H, s, 3-CH-pyrazole), 7.85 (1H, s, 5-CH-pyrazole);
13C{1H} NMR (CDCl3, 125 MHz): d=56.2, 123.6, 125.5,
126.5, 126.4, 127.8, 128.2, 128.8, 128.9, 132.5, 136.4, 137.0;
MS (EI): m/z=234 (M+); high resolution MS: m/z=
1808C. H NMR (CDCl3, 500 MHz): d=3.92 (3H, s, OCH3),
7.26–7.29 (1H, m, Ar-H), 7.39 (2H, t, J=8 Hz, Ar-H), 7.53–
7.55 (2H, m, Ar-H), 7.80–7.82 (2H, m, Ar-H), 8.13–8.15
(2H, m, Ar-H), 8.01 (1H, s, 3-CH pyrazole), 8.21 (1H, d,
J=0.5 Hz, 5-CH pyrazole); 13C{1H] NMR (CDCl3,
125 MHz): d=52.2, 118.1, 123.2, 125.7, 125.8, 127.2, 127.9,
129.0, 131.2, 131.6, 139.7, 143.1, 166.3; MS (EI): m/z=278
(M+); high resolution MS: m/z=279.1131, calcd. for
+
+
235.1238, calcd. for C16H15N2 : 235.1235.
C17H15N2O2 : 279.1134.
1-(4-Methoxyphenyl)-4-phenylpyrazole (3g): A reaction
using the general conditions was carried out with tert-butyl
isonitrile (171 mL, 1.5 mmol), cyclohexylamine (99 mg,
1,4-Diphenyl-5-methylpyrazole (3j): A reaction using the
general conditions was carried out with tert-butyl isonitrile
(136 mL, 1.2 mmol), aniline (92 mg, 1 mmol), 1-phenylpro-
1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti
G
pyne (116 mg, 1 mmol), and TiACTHNGUTRENNU(G NMe2)2ACHTUNGTREN(NGNU dpma) (1, 32.3 mg,
A
0.1 mmol) in toluene (2 mL) and was heated for 48 h at
1008C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was 10–15% ethyl acetate/hexanes, which afford-
ed the desired compound as a pale yellow solid; yield:
95 mg (40%); mp 150–1528C (Lit.[32] mp: 159–1608C).
1H NMR (CDCl3, 500 MHz): d=2.42 (3H, s, Me), 7.28 (1H,
tt, J=7 and 2 Hz, Ar-H), 7.37–7.44 (5H, m, Ar-H), 7.49
(4H, d, J=4.5 Hz, Ar-H), 7.77 (1H, s, 3-CH-pyrazole);
13C{1H} NMR (CDCl3, 125 MHz): d=12.0, 122.0, 125.1,
126.4, 127.8, 127.8, 128.7, 129.1, 133.5, 135.3, 139.2, 139.9;
MS (EI): m/z=234 (M+).
heated for 24 h at 1008C. Volatiles were removed, and 4-me-
thoxyphenylhydrazine hydrochloride (261 mg, 1.5 mmol) in
dry pyridine (3 mL) was added. The mixture was heated to
1508C for 24 h. Purification was accomplished by column
chromatography on neutral alumina. The eluent was 15%
ethyl acetate/hexanes, which afforded the desired compound
as a white solid; yield: 110 mg (44%); mp 124–1258C.
1H NMR (CDCl3, 500 MHz): d=3.87 (3H, s, OMe), 7.0–7.02
(2H, m, Ar-H), 7.28 (1H, tt, J=7.5 and 1 Hz, Ar-H), 7.41
(2H, t, J=8 Hz, Ar-H), 7.57 (2H, dd, J=8 and 1 Hz, Ar-H),
7.64–7.66 (2H, m, Ar-H), 7.98 (1H, d, J=0.5 Hz, 3-CH-pyr-
azole), 8.08 (1H, d, J=0.5 Hz, 5-CH-pyrazole); 13C{1H}
NMR (CDCl3, 125 MHz): d=55.5, 114.5, 120.7, 123.4, 124.5,
125.6, 126.7, 128.9, 132.2, 133.9, 138.3, 158.3; MS (EI): m/z=
250 (M+); high resolution MS: m/z=251-1169, calcd. for
C16H15N2O+: 251.1184.
4,5-Diethyl-1-phenylpyrazole (3k): A reaction using the
general conditions was carried out with tert-butyl isonitrile
(171 mL, 1.5 mmol), aniline (92 mg, 1 mmol), 3-hexyne
1-(4-Cyanophenyl)-4-phenylpyrazole (3h):
A
reaction
(82 mg, 1 mmol), and TiACHTUNGTRENU(NG NMe2)2ACHTUNGTREN(NUNG dpm) (2, 30.8 mg,
using the general conditions was carried out with tert-butyl
isonitrile (171 mL, 1.5 mmol), cyclohexylamine (99 mg,
0.1 mmol) in toluene (2 mL) and was heated for 48 h at
1108C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was hexanes:ethyl acetate 9:1, which afforded
the desired compound as a yellow-red liquid; yield: 74 mg
(37%). 1H NMR (CDCl3, 500 MHz): d=1.03 (3H, t, J=
7.5 Hz, 4-CH2CH3), 1.23 (3H, t, J=7.5 Hz, 5-CH2CH3), 2.47
(2H, q, J=7.5 Hz, 4-CH2CH3), 2.64 (2H, q, J=7.5 Hz, 5-
CH2CH3) 7.34–7.45 (5H, m, Ar-H), 7.46 (1H, s, 3-CH-pyra-
zole); 13C{1H} NMR (CDCl3, 125 MHz): d=13.8, 15.2, 17.1,
17.6, 121.0, 125.3, 127.6, 129.0, 139.2, 140.4, 140.9; MS (EI):
m/z=200 (M+); high resolution MS: m/z=201.1395, calcd.
1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti
ACHTUGNRTEN(NUGN NMe2)2
ACHTUNGTRENNUNG(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was
heated for 24 h at 1008C. Volatiles were removed, and 4-cy-
anophenylhydrazine hydrochloride (255 mg, 1.5 mmol) in
dry pyridine (3 mL) was added. The mixture was heated to
1508C for 24 h. Purification was accomplished by column
chromatography on neutral alumina. The eluent was hex-
ACHTUNGTRENNUNGanes:ethyl acetate 4:1, which afforded the desired com-
pound as a white solid; yield: 100 mg (41%); mp 166–
1
1678C. H NMR (CDCl3, 500 MHz): d=7.27–7.31 (1H, m,
Ar-H), 7.40 (2H, t, J=8 Hz, Ar-H), 7.53–7.54 (2H, m, Ar-
H), 7.74–7.76 (2H, m, Ar-H), 7.85–7.87 (2H, m, Ar-H), 8.02
(1H, s, 3-CH pyrazole), 8.18 (1H, d, J=0.5 Hz, 5-CH pyra-
zole); 13C{1H} NMR (CDCl3, 125 MHz): d=109.6, 118.3,
118.7, 123.0, 125.8, 126.2, 127.4, 129.0, 131.2, 133.6, 140.2,
142.8; MS (EI): m/z=245 (M+); high resolution MS: m/z=
+
for C13H17N2 : 201.1392.
1,4,5-Triphenylpyrazole (3l): A reaction using the general
conditions was carried out with tert-butyl isonitrile (171 mL,
1.5 mmol), aniline (92 mg, 1 mmol), diphenylacetylene
+
246.1040, calcd. for C16H12N3 : 246.1031.
(174 mg, 1 mmol), and TiACHTGUNTREN(NUG NMe2)2ACHTUNGTREN(NUNG dpm) (2, 61.6 mg,
1-(4-Methylcarboxylphenyl)-4-phenylpyrazole (3i): A re-
action using the general conditions was carried out with tert-
butyl isonitrile (171 mL, 1.5 mmol), cyclohexylamine (99 mg,
0.2 mmol) in toluene (2 mL) and was heated for 48 h at
1408C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was hexanes:ethyl acetate 9:1, which afforded
the desired compound as a pale pink solid; yield: 71 mg
(24%); mp 202–2038C (Lit.[33] mp: 197–1988C). 1H NMR
(CDCl3, 500 MHz): d=7.16–7.35 (15H, m, Ar-H), 7.94 (1H,
s, 3-CH pyrazole); 13C{1H} NMR (CDCl3, 125 MHz): d=
122.4, 125.1, 126.4, 127.2, 128.0, 128.4, 128.4, 128.6, 128.7,
130.2, 130.4, 132.8, 139.2, 139.7, 139.9; MS (EI): m/z=296
1 mmol), phenylacetylene (102 mg, 1 mmol), and Ti
ACHTUGNRTEN(NUGN NMe2)2
ACHTUNGTRENNUNG(dpma) (32.3 mg, 0.1 mmol) in toluene (2 mL) and was
heated for 24 h at 1008C. Volatiles were removed, and
methyl 4-hydrazinylbenzoate hydrochloride (303 mg,
1.5 mmol) in dry pyridine (3 mL) was added. The mixture
was heated to 1508C for 24 h. Purification was accomplished
by column chromatography on neutral alumina. The eluent
was hexanes:ethyl acetate 4:1, which afforded the desired
compound as a white solid; yield: 108 mg (39%); mp 179–
Adv. Synth. Catal. 2009, 351, 2013 – 2023
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2019

Supriyo Majumder et al.
FULL PAPERS
(M+); high resolution MS: m/z=297.1388, calcd. for
C21H17N2 : 297.1392.
140.1; MS (EI): m/z=333 (M+); high resolution MS: m/z=
334.2291, calcd. for C22H28N3 : 334.2283.
+
+
1-Phenyl-4-(p-tolyl)pyrazole (3m): A reaction using the
general conditions was carried out with tert-butyl isonitrile
(171 mL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), p-tol-
1-Phenyl-4-(4-methoxyphenyl)pyrazole (3p): A reaction
using the general conditions was carried out with tert-butyl
isonitrile (171 mL, 1.5 mmol), cyclohexylamine (99 mg,
1 mmol), 4-methoxyphenylacetylene (132 mg, 1 mmol), and
ylacetylene (116 mg, 1 mmol), and TiACHTNUGRTENNUG(NMe2)2ACHTUNGTRNE(NUGN dpma) (1,
32.3 mg, 0.1 mmol) in toluene (2 mL) and was heated for
24 h at 1008C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was hexanes:ethyl acetate 9:1, which afforded
the desired compound as a pale yellow solid; yield: 96 mg
(41%); mp 120–1218C (Lit.[34] mp: 127–1288C). 1H NMR
(CDCl3, 500 MHz): d=2.36 (3H, s, CH3), 7.20 (2H, d, J=
8 Hz, Ar-H), 7.28 (1H, tt, J=7.5 and 1 Hz, 4-H-Ph), 7.43–
7.47 (4H, m, Ar-H), 7.71–7.73 (2H, m, Ar-H), 7.97 (1H, d,
J=0.5 Hz, 3-CH-pyrazole), 8.11 (1H, d, J=0.5 Hz, 5-CH-
pyrazole); 13C{1H} NMR (CDCl3, 125 MHz): d=21.1, 118.9,
123.0, 124.9, 125.6, 126.4, 129.1, 129.4, 129.6, 136.5, 138.7,
140.1; MS (EI): m/z=234 (M+); high resolution MS: m/z=
TiACTHUNGTRENU(NG NMe2)2ACHTUNGTREN(NGNU dpm) (2, 30.8 mg, 0.1 mmol) in toluene (2 mL)
and was heated for 24 h at 1008C. Volatiles were removed,
and phenylhydrazine (162 mg, 1.5 mmol) in dry pyridine
(3 mL) was added. The mixture was heated to 1508C for
24 h. Purification was accomplished by column chromatogra-
phy on neutral alumina. The eluent was hexanes:ethyl ace-
tate 9:1, which afforded the desired compound as a white
solid; yield: 94 mg (38%); mp 136–1388C (Lit.[35] mp: 138–
1408C). 1H NMR (CDCl3, 500 MHz): d=3.82 (3H, s,
OCH3), 6.92–6.94 (2H, m, Ar-H), 7.26–7.29 (1H, m, Ar-H),
7.43–7.47 (4H, m, Ar-H), 7.70–7.72 (2H, m, Ar-H), 7.92
(1H, s, 3-CH pyrazole), 8.06 (1H, d, J=1 Hz, 5-CH pyra-
zole); 13C{1H} NMR (CDCl3, 125 MHz): d=55.2, 114.3,
118.9, 122.6, 124.56, 124.58, 126.3, 126.8, 129.3, 138.4, 139.9,
158.6; MS (EI): m/z=250 (M+); high resolution MS: m/z=
251.1185, calcd. for C16H15N2O+: 251.1184.
+
235.1242, calcd. for C16H15N2 : 235.1235.
1-Phenyl-4-butylpyrazole (3n): A reaction using the gener-
al conditions was carried out with tert-butyl isonitrile
(171 mL, 1.5 mmol), cyclohexylamine (99 mg, 1 mmol), 1-
1-Phenyl-5-[3-(tert-butyldimethylsiloxy)propyl]pyrazole
(3q): A reaction using the general conditions was carried
out with tert-butyl isonitrile (171 mL, 1.5 mmol), aniline
(93 mg, 1 mmol), tert-butyldimethyl(pent-4-ynyloxy)silane
hexyne (82 mg, 1 mmol), and TiACHTNUTRGENNUG(NMe2)2ACHTUNGTREN(NGUN dpm) (2, 30.8 mg,
0.1 mmol) in toluene (2 mL) and was heated for 24 h at
1008C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was hexanes:ethyl acetate 9:1, which afforded
the desired compound as a yellow-red liquid; yield: 56 mg
(28%). 1H NMR (CDCl3, 500 MHz): d=0.96 (3H, t, J=
(198 mg, 1 mmol), and TiACHTUNGTRENU(NG NMe2)2ACHTUNGTREN(NGNU dpma) (1, 32.3 mg,
0.1 mmol) in toluene (2 mL) and was heated for 24 h at
1008C. Volatiles were removed, and phenylhydrazine
(162 mg, 1.5 mmol) in dry pyridine (3 mL) was added. The
mixture was heated to 1508C for 24 h which afforded two
isomer in 6.6:1 ratio. Purification of the major isomer was
accomplished by column chromatography on neutral alumi-
na. The eluent was hexanes:ethyl acetate 9:1, which afford-
ed the major isomer as a yellow-red liquid; yield: (110 mg
(35%). 1H NMR (CDCl3, 500 MHz): Major isomer: d=
0.015 (6H, s, Si-CH3), 0.86 (9H, s, Si-CMe2CH3), 1.79–1.84
(2H, m, CH2CH2CH2OTBS), 2.77 (2H, t, J=7.5 Hz,
7.5 Hz,
CH2CH2CH2CH3),
1.39–1.46
(2H,
m,
CH2CH2CH2CH3), 1.58–1.65 (2H, m, CH2CH2CH2CH3),
2.55 (2H, t, J=7.5 Hz, CH2CH2CH2CH3), 7.26 (1H, tt, J=
7.5 and 1 Hz, Ar-H), 7.44 (2H, tt, J=7.5 and 0.5 Hz, Ar-H),
7.56 (1H, s, 3-CH-pyrazole), 7.67–7.69 (2H, m, Ar-H), 7.72
(1H, d, J=1 Hz, 5-CH-pyrazole); 13C{1H} NMR (CDCl3,
125 MHz): d=13.8, 22.3, 23.8, 32.9, 118.7, 124.0, 124.6,
125.9, 129.3, 140.3, 140.9; MS (EI): m/z=200 (M+).
1,4-Diphenyl-5-(3-N,N-diethylamino-n-propyl)pyrazole
(3o): A reaction using the general conditions was carried
out with tert-butyl isonitrile (85 mL, 0.75 mmol), aniline
(46 mL, 0.5 mmol), N,N-diethyl-5-phenylpent-4-yn-1-amine
CH2CH2CH2OTBS),
3.62
(2H,
t,
J=6 Hz,
CH2CH2CH2OTBS), 6.23 (1H, d, J=2 Hz, 4-CH pyrazole),
7.37–7.40 (1H, m, Ar-H), 7.44–7.48 (4H, m, Ar-H), 7.60
(1H, d, J=1.5 Hz, 3-CH pyrazole); 13C{1H} NMR (CDCl3,
125 MHz): d=À5.4, 18.1, 22.5, 25.8, 31.8, 61.8, 105.3, 125.2,
127.6, 128.9, 139.7, 139.9, 143.1; MS (EI): m/z=317 (M+ +
H); high resolution MS: m/z=317.2055, calcd. for
C18H29N2OSi+: 317.2049.
(107.5 mg, 0.5 mmol), and Ti
(NMe2)
E
3-Butylpyrazole (3r): A reaction using the general condi-
tions was carried out with tert-butyl isonitrile (565 mL,
5 mmol), aniline (456 mL, 5 mmol), 1-hexyne (575 mL,
0.05 mmol) in toluene (1 mL) and was heated for 48 h at
1108C. Volatiles were removed, and phenylhydrazine
(81 mg, 0.75 mmol) in dry pyridine (1.5 mL) was added. The
mixture was heated to 1508C for 24 h. Purification was ac-
complished by column chromatography on neutral alumina.
The eluent was hexanes:ethyl acetate:triethylamine 74:25:1,
which afforded the compound as a red liquid; yield: 52 mg
(31%). 1H NMR (CDCl3, 500 MHz): d=0.87 (6H, t, J=
7 Hz, CH2CH3), 1.48–1.54 (2H, m, CH2CH2CH2NEt2), 2.24
(2H, t, J=7 Hz, CH2CH2CH2NEt2), 2.31 (4H, q, J=7 Hz,
CH2CH3), 2.87 (2H, t, J=8 Hz, CH2CH2CH2NEt2), 7.29–
7.33 (1H, m, Ar-H), 7.43–7.48 (5H, m, Ar-H), 7.49–7.51
(4H, m, Ar-H), 7.76 (1H, s, 3-CH pyrazole); 13C{1H} NMR
(CDCl3, 125 MHz): d=11.4, 22.6, 26.1, 46.5, 52.1, 121.5,
125.8, 126.4, 127.9, 128.1, 128.6, 129.0, 133.7, 139.4, 139.9,
5 mmol), and TiACHTNUGRTENNUG(NMe2)2ACHTUGNTREN(NUNG dpma) (1, 162 mg, 0.5 mmol) in tol-
uene (10 mL) and was heated for 24 h at 1008C. Volatiles
were removed, and hydrazine hydrate (375 mg, 7.5 mmol) in
dry pyridine (15 mL) was added. The mixture was heated to
1508C for 12 h. Purification was accomplished by Kugelrohr
distillation, which afforded the desired compound as a mix-
ture of two isomers in a 6:1 ratio as a pale yellow liquid;
yield: 328 mg, (53%). Data for the major isomer:
1H NMR[36] (CDCl3, 500 MHz): d=0.91 (3H, t, J=7.5 Hz,
CH2CH2CH2CH3), 1.34–1.38 (2H, m, CH2CH2CH2CH3),
1.59–1.65 (2H, m, CH2CH2CH2CH3), 2.66 (2H, t, J=8.0 Hz,
CH2CH2CH2CH3), 6.06 (1H, d, J=2 Hz, 4-CH-pyrazole),
7.47 (1H, d, J=2 Hz, 5-CH-pyrazole); 13C{1H} NMR
2020
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2013 – 2023

Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent Coupling Reaction
FULL PAPERS
(CDCl3, 125 MHz): d=13.8, 22.3, 26.4, 31.5, 103.4, 121.3;
MS (EI): m/z =124 (M+).
4-Butylpyrazole (3s): A reaction using the general condi-
tions was carried out with tert-butyl isonitrile (850 mL,
7.5 mmol), cyclohexylamine (570 mL, 5 mmol), 1-hexyne
500 MHz): d=2.64–2.70 (2H, m, N-CH2CH2CH2), 3.08 (2H,
t, J=7.5 Hz, N-CH2CH2CH2), 4.16 (2H, t, J=7.5 Hz, N-
CH2CH2CH2), 7.16 (1H, tt, J=7 and 1 Hz, Ar-H), 7.33 (2H,
d, J=7.5 Hz, Ar-H), 7.42–7.44 (2H, m, Ar-H), 7.79 (1H, s,
3-CH-pyrazole); 13C{1H} NMR (CDCl3, 125 MHz): d=23.8,
26.4, 47.6, 115.3, 125.0, 125.6, 128.8, 133.4, 140.9, 142.6; MS
(EI): m/z=184 (M+).
(575 mL, 5 mmol), and TiACTHNUTRGENNUG(NMe2)2ACHTUNGTREN(NGUN dpm) (2, 154 mg,
0.5 mmol) in toluene (10 mL) and was heated for 24 h at
1008C. Volatiles were removed, and hydrazine hydrate
(375 mg, 7.5 mmol) in dry pyridine (15 mL) was added. The
mixture was heated to 1508C for 12 h. Purification was ac-
complished by Kugelrohr distillation, which afforded the de-
sired compound as a pale yellow liquid;[23] yield: 167 mg
(27%). 1H NMR (CDCl3, 500 MHz): d=0.90 (3H, t, J=
Supporting Information
Tabular data for the X-ray diffraction experiment on 3j.
CCDC 734720 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif. 1H and 13C NMR
spectra for the pyrazoles 3. GC FID traces for the pyrazole
products with the exception of NH-pyrazoles, 3o, and witha-
somnine, which did not pass through our GC column. MS
EI fragmentation pattern for withasomnine (6).
7.5 Hz,
CH2CH2CH2CH3),
1.30–1.37
(2H,
m,
CH2CH2CH2CH3), 1.50–1.56 (2H, m, CH2CH2CH2CH3),
2.47 (2H, t, J=7.0 Hz, CH2CH2CH2CH3), 7.37 (2H, s, CH-
pyrazole), 9.43 (1H, br s, NH); 13C{1H} NMR (CDCl3,
125 MHz): d=13.8, 22.3, 23.6, 33.1, 121.4, 132.6; MS (EI):
m/z=124 (M+).
Withasomnine(6) Synthesis
Acknowledgements
5-[3-(tert-Butyldimethylsilyloxy)propyl]-4-phenyl-1H-pyra-
zole (5): A reaction using the general conditions was carried
out with tert-butyl isonitrile (1.29 mL, 7.5 mmol), aniline
(465 mg, 5 mmol), 5-(tert-butyldimethylsilyloxy)-1-phenyl-
The authors thank the National Science Foundation and the
Petroleum Research Fund administered by the American
Chemical Society for financial support. KG would also like
to thank the Ronald E. McNair program at Michigan State
for support.
pent-1-yne[23] (1.37 g, 5 mmol), and Ti
ACHTNUTRGENNUG(NMe2)2CAHTUNGTRENN(UGN dpm) (2,
154 mg, 0.5 mmol) in toluene (5 mL) and was heated for
48 h at 1108C. Volatiles were removed, and hydrazine hy-
drate (375 mg, 7.5 mmol) in pyridine (15 mL) was added.
The mixture was heated to 1508C for 24 h. Purification was
accomplished by column chromatography on neutral alumi- References
na. The eluent was initially hexanes:ethyl acetate 1:1 fol-
lowed by 5% methanol in ethyl acetate, which afforded the
desired compound as a viscous dark red oil; yield: 552 mg
(35%). 1H NMR (CDCl3, 500 MHz): d=0.055 (6H, s,
Si-CH3), 0.89 (9H, s, Si-CCH3), 1.85–1.91 (2H, m,
[1] For selected recent examples of catalyzed multicompo-
nent couplings to generate heterocycles see a) E. H.
Krenske, K. N. Houk, B. A. Arndtsen, D. J. St. Cyr, J.
Am. Chem. Soc. 2008, 130, 10052; b) Y. Lu, B. A.
Arndtsen, Angew. Chem. 2008, 120, 5510; Angew.
Chem. Int. Ed. 2008, 47, 5430; c) D. A. Black, R. E.
Beveridge, B. A. Arndtsen, J. Org. Chem. 2008, 73,
1906; d) J. Kalisiak, K. B. Sharpless, V. V. Fokin, Org.
Lett. 2008, 10, 3171; e) N. Isambert, R. Lavilla, Chem.
Eur. J. 2008, 14, 8444; f) T. L. Church, C. M. Byrne,
E. B. Lobkovsky, G. W. Coates, J. Am. Chem. Soc.
2007, 129, 8156; g) D. M. D’Souza, T. J. Mꢂller, Chem.
Soc. Rev. 2007, 36, 1095; h) R. Dhawan, R. D. Dghaym,
D. J. St. Cyr, B. A. Arndtsen, Org. Lett. 2006, 8, 3927;
i) A. R. Siamaki, B. A. Arndtsen, J. Am. Chem. Soc.
2006, 128, 6050; j) K. Mitsudo, P. Thansandote, T. Wil-
helm, B. Mariampillai, M. Lautens, Org. Lett. 2006, 8,
3939; k) J. Zhu, H. Bienaymꢃ, (Eds.), Multicomponent
Reactions, Wiley-VCH, Weinheim, 2005; l) G. Balme,
Angew. Chem. 2004, 116, 6396; Angew. Chem. Int. Ed.
2004, 43, 6238; m) S. Kamijo, T. Jin, Z. B. Huo, Y. Ya-
mamoto, J. Org. Chem. 2004, 69, 2386; n) S. Kamijo, T.
Jin, Y. Yamamoto, Tetrahedron Lett. 2004, 45, 689; o) S.
Kamijo, T. Jin, Z. Huo, Y. Yamamoto, J. Am. Chem.
Soc. 2003, 125, 7786; p) E. Bossharth, P. Desbordes, N.
Monteiro, G. Balme, Org. Lett. 2003, 5, 2441;
q) M. S. M. Ahmed, K. Kobayashi, A. Mori, Org. Lett.
2005, 7, 4487; r) J. P. Stonehouse, D. S. Chekmarev,
N. V. Ivanova, S. Lang, G. Pairaudeau, N. Smith, M. J.
CH2CH2CH2OTBDMS),
CH2CH2CH2OTBDMS),
2.91
3.69
(2H,
(2H,
t,
t,
J=7.5 Hz,
J=6 Hz,
CH2CH2CH2OTBDMS), 7.23–7.26 (2H, m, Ar-H, NH),
7.36–7.39 (4H, m, Ar-H), 7.64 (1H, s, 3-CH-pyrazole);
13C{1H} NMR (CDCl3, 125 MHz): d=À5.4, 18.3, 22.2, 25.9,
31.4, 62.6, 119.6, 126.2, 127.7, 128.2, 128.6, 131.5, 133.6; MS
(EI): m/z=316 (M+); high resolution MS: m/z=317.2041,
calcd. for C18H29N2OSi+: 317.2049.
Withasomnine (6): Under nitrogen
5
(140 mg,
0.443 mmol) in 5 mL CH2Cl2 was treated with BBr3 (1.1 mL,
1M soln in CH2Cl2, 1.1 mmol). The reaction mixture was
stirred at room temperature for 48 h and then quenched
with saturated NaHCO3. The organic layer was separated,
dried over Na2SO4, and concentrated under rotary evapora-
tion. The crude product was dissolved in absolute EtOH
(10 mL) and treated with sodium ethoxide (240 mg,
3.53 mmol). The mixture was heated to reflux for 20 h and
then cooled to room temperature. The volatiles were re-
moved under rotary evaporation. The crude mixture was
dissolved in CH2Cl2, washed with water, dried over Na2SO4,
and concentrated under rotary evaporation. The product
was purified by column chromatography on alumina using
ethyl acetate:hexanes 1:1 with gradient to methanol:ethyl
acetate 1:4 to obtain withasomnine; yield: 58 mg (71%); mp
113–1158C (Lit.[3d] mp: 117–1188C). 1H NMR (CDCl3,
Adv. Synth. Catal. 2009, 351, 2013 – 2023
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2021

Supriyo Majumder et al.
FULL PAPERS
Stocks, S. I. Sviridov, L. M. Utkinab, Synlett 2008, 100;
s) H.-L. Liu, H.-F. Jiang, M. Zhang, W.-J. Yao, Q.-H.
Zhu, Z. Tang, Tetrahedron Lett. 2008, 49, 3805; t) B.
Willy, T. J. J. Mꢂller, Eur. J. Org. Chem. 2008, 4157.
[2] C. Lamberth, Heterocycles 2007, 71, 1467.
[3] For papers on withasomnineꢄs isolation from natural
sources and biological studies see a) S. A. Adesanya, R.
Nia, C. Fontaine, M. Pais, Phytochemistry 1994, 35,
1053; b) A. A. Wube, E.-M. Wenzig, S. Gibbons, K.
Asres, R. Bauer, F. Bucar, Phytochemistry 2008, 69,
982; c) P. J. Houghton, R. Pandey, J. E. Hawkes, Phyto-
chemistry 1994, 35, 1602; d) H.-B. Schroter, D. Neu-
mann, A. R. Katritzky, R. J. Swinbourne, Tetrahedron
1966, ##22##2895; e) V. Ravikanth, P. Ramesh, P. V.
Diwan, Y. Venkateswarlu, Biochem. Syst. Ecol. 2001,
29, 753.
more specifically to 1,3-diimines reactions related to
those here, see: c) J. Barluenga, E. Rubio, V. Rubio, L.
Muniz, M. J. Iglesias, V. Gotor, J. Chem. Res. Synop.
1985, 124; d) J. Barluenga, M. J. Iglesias, V. Gotor, Syn-
thesis 1987, 662; e) V. Gotor, R. Brieva, A. Aguirre, S.
Garcia-Granda, F. Gomez-Beltran, Heterocycles 1989,
29, 1695; f) J. Barluenga, J. F. Lꢆpez-Ortiz, M. Tomꢅs,
V. Gotor, J. Chem. Soc. Perkin Trans. 1 1981, 1891; g) J.
Barluenga, J. Jardꢆn, V. Rubio, V. Gotor, J. Org. Chem.
1983, 48, 1379.
[18] None of the reaction times have been fully optimized.
Reactions were generally run for about 24 h.
[19] Different amines were used for the two reactions in
this scheme due to complications. Aniline seems to
give superior yields for the multicomponent coupling
reactions with 1. With catalyst 2, when aniline is used
as the substrate in these reactions a different product
due to a 4-component coupling reaction is a significant
by-product. The 4-CC product is being reported sepa-
rately: E. Barnea, S. Majumder, R. J. Staples, A. L.
Odom, Organometallics 2009, 28, 2876.
[20] At room temperature the proton migration between
pyrazole nitrogens is often rapid on the NMR time-
scale. R. M. Claramunt, C. Lopez, M. D. Santa Maria,
E. Sanz, J. Elguero, Prog. Nucl. Mag. Reson. Spectr.
2006, 49, 169.
[4] C. Cao, Y. Shi, A. L. Odom, J. Am. Chem. Soc. 2003,
125, 2880.
[5] For a review on azadienes in synthesis see a) S. Jayaku-
mar, M. P. S. Ishar, M. P. Mahajan, Tetrahedron 2002,
58, 379; b) L. A. Calvo, A. M. Gonzalez-Nogal, A.
Gonzalez-Ortega, M. C. SaÇudo, Tetrahedron Lett.
2001, 42, 8981 for related silyl isoxazole chemistry.
[6] a) J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th edn.,
Blackwell Publishing, 2000; b) K. Makino, H. S. Kim,
Y. Kurasawa, J. Heterocycl. Chem. 1999, 36, 321;
c) M. A. Halcrow Dalton Trans. 2009, 2059.
[21] This compound was not isolated in pure form but was
1
[7] A. L. Odom, Dalton Trans. 2005, 225.
observed by H NMR. The ratio given is from NMR in-
[8] D. C. Bradley, I. M. Thomas, J. Chem. Soc. 1960, 3859.
[9] Y. Li, Y. Shi, A. L. Odom, J. Am. Chem. Soc. 2004, 126,
1794.
tegration.
[22] For some additional references to syntheses of 4-phe-
nylpyrazole not discussed explicitly, see: a) C. Cativiela,
M. D. Diaz de Villegas, M. P. Gainza, Synth. Commun.
1987, 17, 165; b) H. Neunhoeffer, M. Clausen, H. D.
Voetter, H. Ohl, C. Krueger, K. Angermund, Liebigs
Ann. Chem. 1985, 1732; c) F. C. Escribano, M. P. D. Al-
cantara, A. Gomez-Sanchez, Tetrahedron Lett. 1988, 29,
6001.
[23] For a very nice synthesis applicable to a few 4-(alkyl)-
pyrazoles involving Vilsmeier formylation, see: D. L.
Reger, J. R. Gardinier, T. C. Grattan, M. R. Smith,
M. D. Smith, New J. Chem. 2003, 27, 1670.
[10] a) P. J. Walsh, A. M. Baranger, R. G. Bergman, J. Am.
Chem. Soc. 1992, 114, 1708; b) A. M. Baranger, P. J.
Walsh, R. G. Bergman, J. Am. Chem. Soc. 1993, 115,
2753; c) P. L. McGrane, M. Jenson, T. Livinghouse, J.
Am. Chem. Soc. 1992, 114, 5459; d) G. Zi, L. L. Blosch,
L. Jia, R. A. Andersen, Organometallics 2005, 24, 4602;
e) J. L. Poise, R. A. Andersen, R. G. Bergman, J. Am.
Chem. Soc. 1998, 120, 13405; f) A. P. Duncan, R. G.
Bergman, Chem. Rec. 2002, 2, 431; g) R. Severin, S.
Doye, Chem. Soc. Rev. 2007, 36, 1407.
[11] A derivative of this metallacycle has recently been iso-
lated and structurally characterized. N. Vujkovic, J. L.
Fillol, B. D. Ward, H. Wadepohl, P. Mountford, L. H.
Gade, Organometallics 2008, 27, 2518.
[24] N. Kudo, M. Perseghini, G. C. Fu, Angew. Chem. 2006,
118, 1304; Angew. Chem. Int. Ed. 2006, 45, 1282. Pro-
tection of the pyrazole NH leads to much higher yields
for the coupling but adds additional steps.
[12] C. Cao, J. T. Ciszewski, A. L. Odom, Organometallics
[25] H. Ichikawa, Y. Ohno, Y. Usami, M. Arimoto, Hetero-
cycles 2006, 68, 2247.
2001, 20, 5011.
[13] Y. Li, A. Turnas, J. T. Ciszewski, A. L. Odom, Inorg.
Chem. 2002, 41, 6298.
[26] a) S. M. Allin, W. R. S. Barton, W. R. Bowman, T. McI-
nally, Tetrahedron Lett. 2002, 43, 4191; b) O. Kulinko-
vich, N. Masalov, V. Tyvorskii, N. De Kimpe, M. Kep-
pens, Tetrahedron Lett. 1996, 37, 1095; c) D. Rangana-
than, S. Bamezai, Synth. Commun. 1985, 15, 259; d) A.
Guzman-Perez, L. A. Maldonado, Synth. Commun.
1991, 21, 1667; e) A. Morimoto, K. Noda, T. Watanabe,
H. Takasugi, Tetrahedron Lett. 1968, 9, 5707; f) S.
Takano, Y. Imamura, K. Ogasawara, Heterocycles 1982,
19, 1223; g) S. M. Allin, W. R. S. Barton, W. R.
Bowman, E. Bridge, M. R. J. Elsegood, T. McInally, V.
McKee, Tetrahedron 2008, 64, 7745.
[14] a) Y. Shi, C. Hall, J. T. Ciszewski, C. Cao, A. L. Odom,
Chem. Commun. 2003, 586; b) A. Novak, A. J. Blake,
C. Wilson, J. B. Love, Chem. Commun. 2002, 23, 2796.
[15] B. J. Littler, M. A. Miller, C.-H. Hung, R. W. Wagner,
D. F. OꢄShea, P. D. Boyle, J. S. Lindsey, J. Org. Chem.
1999, 64, 1391.
[16] G. W. Gokel, R. P. Widera, W. P. Weber, Org. Synth.
1976, 55, 96.
[17] For reviews on the extensive work of Barluenga and
co-workers on applications of 1,3-diimines to organic
synthesis see a) J. Barluenga, M. Tomꢅs, Adv. Hetero-
cycl. Chem. 1993, 57, 1; b) J. Barluenga, Bull. Soc.
Chim. Belg. 1988, 97, 545. For some references related
[27] a) Y. Six, Eur. J. Org. Chem. 2003, 1157; b) T. Zheng,
T. S. Narayan, J. M. Schomaker, B. Borhan, J. Am.
Chem. Soc. 2005, 127, 6946.
2022
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2013 – 2023

Pyrazole Synthesis Using a Titanium-Catalyzed Multicomponent Coupling Reaction
FULL PAPERS
[28] See ref.[26a] Their overall yield was 27% in 6 steps if
one includes the synthesis of I(CH2)3SnPh, which does
[32] H. O. House, D. J. Reif, J. Am. Chem. Soc. 1955, 77,
6525.
AHCTUNGTRENNUNG
not seem to be commercially available. J. E. Baldwin,
R. M. Adlington, J. Robertson, Tetrahedron 1989, 45,
909. Their starting material is 4-bromopyrazole, which
is commercially available.
[33] R. Olivera, R. SanMartin, E. Dominguez, J. Org.
Chem. 2000, 65, 7010.
[34] S. Kano, Y. Yuasa, S. Shibuya, S. Hibino, Heterocycles
1982, 19, 1079.
[29] H. Rupe, E. Knup, Helv. Chim. Acta 1927, 10, 299.
[30] J. W. Pavlik, N. Kebede, J. Org. Chem. 1997, 62, 8325.
[31] S. D. Walker, T. E. Barder, J. R. Martinelli, S. L. Buch-
wald, Angew. Chem. 2004, 116, 1907; Angew. Chem.
Int. Ed. 2004, 43, 1871.
[35] T. M. Razler, Y. Hsiao, F. Qian, R. Fu, K. Khan, W.
Doubleday, J. Org. Chem. 2009, 74, 1381.
[36] R. Huisgen, J. Koszinowski, A. Ohta, R. Schiffer,
Angew. Chem. 1980, 92, 198; Angew. Chem. Int. Ed.
Engl. 1980, 19, 202.
Adv. Synth. Catal. 2009, 351, 2013 – 2023
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2023