Single-step synthesis of pyrazoles using titanium catalysis

Article abstract of DOI:10.1039/c1cc15809k

A simple titanium complex catalyzes the coupling of alkynes, isonitriles, and monosubstituted hydrazines to generate substituted pyrazoles in a single step.

Full text of DOI:10.1039/c1cc15809k

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Single-step synthesis of pyrazoles using titanium catalysisw
Amila A. Dissanayake and Aaron L. Odom*
Received 19th September 2011, Accepted 23rd October 2011
DOI: 10.1039/c1cc15809k
A simple titanium complex catalyzes the coupling of alkynes,
isonitriles, and monosubstituted hydrazines to generate substituted
pyrazoles in a single step.
Pyrazoles constitute a commercially important class of hetero-
cycles found in pharmaceuticals, herbicides, fungicides, and
insecticides,1 which are accessed using a variety of different
synthetic routes.2 In previous work, our group has developed
titanium-based catalysts for one-pot, two-step heterocyclic
syntheses.3 Titanium catalysts are being sought because they
are inexpensive, nontoxic, and the catalysts are readily removed
from the products.4 Here, we describe a new multicomponent
coupling strategy for the single-step synthesis of pyrazoles
enabled by a new, robust catalyst system.
Previous research on hydrazine additions to alkynes, hydro-
hydrazination,5 has focused on, for the most part, addition of
1,1-disubstituted hydrazines to alkynes. Titanium-based catalysts
Fig. 1 Synthesis of 1 and an ORTEP diagram of the structure from
can accomplish this reaction, which is also a new route to
indoles,6,7 with either terminal alkynes or internal alkynes.
Zinc-based compounds can also catalyze additions of hydrazines
to alkynes to produce indoles, but the reaction is apparently
limited to terminal alkynes.8
X-ray diffraction.
The structure (Fig. 1) was obtained from X-ray diffraction
of pseudo-octahedral 1 (see the Supplementary Information
for details).z The more strongly donating dimethylamido ligands
are trans to the neutral pyridine donors, placing the pyrrolyl
ligands mutually trans. As is typical, the Ti–N(pyrrolyl) distances
average 2.111(1) A, significantly longer than the Ti–NMe2
bonds, 1.910(2) A. The Ti–N(pyridyl) distances average
2.260(2) A. All these can be compared with the estimated
single- and double-bond distances for Ti–N bonds according
In a variant of the hydrohydrazination reaction, we showed
titanium-catalysts can convert alkynes, isonitriles, and hydrazines
to 1,3-iminohydrazones.9 Unfortunately, that catalysis was
limited to 1,1-disubstituted hydrazines as starting materials
using previous catalysts.10 The apparent cause of the inactivity
in some of the previous systems was the removal of all the
ancillary ligands by more aggressive monsubstituted hydrazines.
The loss of the ancillaries likely leads to inactive bridged
hydrazido complexes. This hypothesis is put forward because
of the large amounts of free ligand observed under attempted
catalyses.
We have discovered that 2-(20-pyridyl)-3,5-dimethylpyrrole
(Hpypyr), which is prepared11,12 in a single step from commercially
available acetylacetone and 2-aminomethylpyridine,13 can be
used to generate (Fig. 1) Ti(NMe2)2(pypyr)2 (1), which efficiently
catalyzes the multicomponent coupling of alkynes, isonitriles, and
monosubstituted hydrazines to provide pyrazoles in a single step.
to Pyykko’s radii of 2.07 and 1.77 A, respectively.14
¨
The proposed catalytic cycle for the titanium-catalyzed multi-
component coupling reaction is shown in Scheme 1. We suggest
the intermediacy of titanium hydrazido(2ꢀ) A in the reaction. It
is well known that isolable, terminal titanium hydrazido(2ꢀ)
ligands can be formed using the reaction of hydrazines with
bis(dimethylamido) complexes.15 The hydrazido(2ꢀ) A could
then undergo [2+2]-cycloaddition with the alkyne to give B, a
reaction observed in related systems.16,17 Isonitrile can 1,1-insert
into the Ti–C bond in B to give the 5-membered metallacycle
C.16,18 Hydrazine protonolysis of metallacycle C would give D;
a compound bearing a nitrogen-based acetylacetonate analo-
gue similar to the one in D has been observed in 1,1-disub-
stituted hydrazine multicomponent coupling reactions.16
Proton migration from the hydrazido in D could liberate
imine E, which would cyclize to the pyrazole product with
loss of H2NR4 to aromatize the heterocycle.
Michigan State University, Department of Chemistry East Lansing,
MI 48823, USA. E-mail: odom@chemistry.msu.edu
w Electronic supplementary information (ESI) available: Details for the
preparation and characterization of compounds. Tables for the X-ray
Diffraction Study on 1. CCDC 845078. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1cc15809k
c
440 Chem. Commun., 2012, 48, 440–442
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Table 1 Pyrazoles prepared using multicomponent couplings with 1y
Hydrazine Alkyne
PhNHNH2
Product
Isolated yield
66%
PhNHNH2
PhNHNH2
71%
55%
PhNHNH2
PhNHNH2
48%
46%
Scheme 1 Proposed catalytic cycle for the synthesis of pyrazoles.
In Table 1, is a listing of the pyrazoles prepared using this
multicomponent methodology during the course of this initial
study.y With catalyst 1, only smaller alkyl- or aryl-substituted
terminal alkynes are applicable.19 In all cases, a single regioisomer
was observed by GC-MS and 1H NMR, and the product
shown was readily isolated by chromatography.
PhNHNH2
PhNHNH2
PhNHNH2
60%
49%
60%
The regioselectivity of the reactions are such that a single
observable isomer is generated. For the substrates examined in
this study, 1,3-disubstituted pyrazoles were the products. In
other words, the favored product isomer is derived from [2+2]-
cycloaddition to place the larger group on the alkyne away from
the metal center in metallacyclobutene B (Scheme 1) such that
R2 is the alkyne substituent and R3 is H in these cases.
For all of the reactions cyclohexylisonitrile was used. In
screening isonitriles, we used the coupling between phenyl-
acetylene, phenylhydrazine, and CNR4 catalyzed by 1. The
isonitriles investigated had R4 = tert-butyl, 2,6-dimethylphenyl,
cyclohexyl, and n-butyl. While cyclohexylisonitrile gave relatively
clean reactivity, reactions employing 2,6-dimethylphenylisonitrile
and n-butylisonitrile resulted in a myriad of unidentified products.
On the other hand, the reaction with tert-butylisonitrile was
relatively clean but did not proceed with as good conversion as
the slightly smaller cyclohexyl derivative.
PhNHNH2
PhNHNH2
47%
75%
X = 4-Br 52%
X = 4-I 62%
X = 4-Me 57%
X = 4-OMe
70%
The synthetic route presented here can be compared with
other syntheses for the same compounds in the literature. As
an example, one could consider alternative routes to 1,3-
diphenylpyrazole. There are a large number of routes previously
published to this simple compound, most involving multistep
procedures.20 Perhaps the most straightforward route involves
addition of phenylhydrazine to phenylpropynone in HCl/MeOH
with microwave heating,21 which gives a 76% yield of the 1,3-
diphenylpyrazole along with a 15% yield of the 1,5-derivative.
As shown, this route presented here involves titanium-catalyzed
coupling of commercially available compounds under thermal
conditions and gave 48% isolated yield of a single regioisomer.
X = 3,5-Cl2
45%
In conclusion, the use of 2-(20-pyridyl)pyrrolyls as ancillaries
on titanium allows 3-component coupling of monosubstituted
hydrazines with alkynes and isonitriles to produce pyrazoles
in a single step. Improvements in catalyst design to increase
the substrate scope and reduce heating times are currently
being sought in different derivatives of this successful
framework.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 440–442 441

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M. Ghedini, Chem. Commun., 2009, 1550; (c) A. T. Luedtke and
K. I. Goldberg, Angew. Chem., Int. Ed., 2008, 47, 7694.
Notes and references
13 For some other 2-(20-pyridyl)pyrroles in metal chemistry see:
(a) M. F. Semmelhack, A. Chlenov and D. M. Ho, J. Am. Chem.
Soc., 2005, 127, 7759; (b) H. Wang, Y. Zeng, J. S. Ma, H. Fu,
J. Yao, A. I. Mikhaleva and B. A. Trofimov, Chem. Commun.,
2009, 5457; (c) J. L. McBee and T. D. Tilley, Organometallics,
2010, 29, 184; (d) J. G. Andino, J. A. Flores, J. A. Karty,
J. P. Massa, H. Park, N. P. Tsvetkov, R. J. Wolfe and
K. G. Caulton, Inorg. Chem., 2010, 49, 7626; (e) J. A. Flores,
J. G. Andino, N. P. Tsvetkov, M. Pink, R. J. Wolfe, A. R. Head,
D. L. Lichenberger, J. Massa and K. G. Caulton, Inorg. Chem.,
2011, 50, 8121.
z Crystal data for 1: C26H34N6Ti,
M = 478.49, monoclinic,
a = 10.7933(11) A, b = 14.4889(14) A, c = 15.8761(16) A, b =
97.072(1)1, U = 2463.9(4) A3, space group P21/c, Z = 4, m(Mo-Ka) =
0.606 mmꢀ1, y range 1.90 to 25.361, 4497 independent reflections
(Rint = 0.0333), GoF = 1.040, wR(F2) = 0.0875, R1 = 0.033.
y General Procedure for Catalyses: A pressure tube with a threaded top
was loaded with a stir bar, toluene (2 mL), cyclohexylisonitrile
(1.5 mmol), hydrazine (1 mmol), alkyne (1 mmol), and 1 (15 mol%,
72 mg). The tube was fitted with a Teflon cap, removed from the dry
box, and heated at 100 1C for 36 h. The compounds were purified by
column chromatography on neutral alumina.
14 P. Pyykko and M. Atsumi, Chem.–Eur. J., 2009, 15, 12770.
¨
1 C. Lamberth, Heterocycles, 2007, 71, 1467.
2 S. Fustero, A. Simon-Fuentes and J. F. Sanz-Cervera, Org. Prep.
Proced. Int., 2009, 41, 253.
3 (a) S. Majumder and A. L. Odom, Tetrahedron, 2010, 66, 3152;
(b) S. Majumder, K. R. Gipson, R. J. Staples and A. L. Odom,
Adv. Synth. Catal., 2009, 351, 2013; (c) S. Majumder, K. R. Gipson
and A. L. Odom, Org. Lett., 2009, 11, 4720.
4 Titanium is the second most abundant transition metal in the
earth’s crust after iron: N. N. Greenwood and A. Earnshaw,
Chemistry of the Elements, Pergamon Press, Oxford, 1984.
5 For a hydrohydrazination based on a Cope variant see F. Loiseau,
C. Clavette, M. Raymond, J.-G. Roveda, A. Burrell and
A. M. Beauchemin, Chem. Commun., 2011, 47, 562; For some
gold-catalyzed reactions see: N. T. Patil and A. Konala, Eur. J.
Org. Chem., 2010, 6831; R. Kinjo, B. Donnadieu and G. Bertrand,
Angew. Chem., Int. Ed., 2011, 50, 5560.
15 (a) Y. Li, Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2004,
126, 1794; (b) S. Patel, Y. Li and A. L. Odom, Inorg. Chem., 2007,
46, 6373; (c) J. D. Selby, M. Feliz, A. D. Schwarz, E. Clot and
P. Mountford, Organometallics, 2011, 30, 2295; (d) T. Janssen,
R. Severin, M. Diekmann, M. Friedmann, D. Haase, W. Saak,
S. Doye and R. Beckhaus, Organometallics, 2010, 29, 1806;
(e) A. J. Clulow, J. D. Selby, M. G. Cushion, A. D. Schwarz and
P. Mountford, Inorg. Chem., 2008, 47, 12049.
16 S. Banerjee and A. L. Odom, Organometallics, 2006, 25, 3099.
17 For examples of [2+2]-cycloadditions with titanium hydrazido(2ꢀ)
complexes see ref. 16 and (a) P. J. Tiong, A. Nova, L. R. Groom,
A. D. Schwarz, J. D. Selby, A. D. Schofield, E. Clot and
P. Mountford, Organometallics, 2011, 30, 1182; (b) A. D. Schofield,
A. Nova, J. D. Selby, C. D. Manley, A. D. Schwarz, E. Clot and
P. Mountford, J. Am. Chem. Soc., 2010, 132, 10484;
(c) K. Weitershaus, J. L. Fillol, H. Wadepohl and L. H. Gade,
Organometallics, 2009, 28, 4747. For a related zirconium study see
T. Gehrmann, J. L. Fillol, S. A. Scholl, H. Wadepohl and L. H. Gade,
Angew. Chem., Int. Ed., 2011, 50, 5757.
18 This insertion intermediate has been observed in the related amine
multicomponent coupling reaction. N. Vujkovic, J. L. Fillol,
B. D. Ward, H. Wadepohl, P. Mountford and L. H. Gade,
Organometallics, 2008, 27, 2518.
19 Using anhydrous hydrazine as substrate resulted only in free ligand
liberated from 1 and other starting materials. For the preparation
of anhydrous hydrazine see: M. R. Smith III, T.-Y. Cheng and
G. L. Hillhouse, J. Am. Chem. Soc., 1993, 115, 8638.
6 (a) C. Cao, Y. Shi and A. L. Odom, Org. Lett., 2002, 4, 2853;
(b) L. Ackermann and R. Born, Tetrahedron Lett., 2004, 45, 9541.
7 For a review see: K. Kruger, A. Tillack and M. Beller, Adv. Synth.
Catal., 2008, 350, 2153.
¨
8 K. Alex, A. Tillack, N. Schwarz and M. Beller, Angew. Chem., Int.
Ed., 2008, 47, 2304. For some related processes to synthesize
pyrazoles from but-4-yn-1-ol see: K. Alex, A. Tillack,
N. Schwarz and M. Beller, Org. Lett., 2008, 10, 2377.
9 S. Banerjee, Y. Shi, C. Cao and A. L. Odom, J. Organomet. Chem.,
2005, 690, 5066. For the amine variant see: C. Cao, Y. Shi and
A. L. Odom, J. Am. Chem. Soc., 2003, 125, 2880.
10 We were able to extend the Ti-catalyzed hydrohydrazination to
monosubstituted hydrazines, but that catalyst system did not
catalyze the iminohydrazination reaction. It is unclear at this
time why Ti(enp)(NMe2)2 catalyzes hydrohydrazination but not
iminohydrazination. S. Banerjee, E. Barnea and A. L. Odom,
Organometallics, 2008, 27, 1005.
11 J. J. Klappa, A. E. Rich and K. McNeill, Org. Lett., 2002, 4, 435.
12 For examples of late metals using this ligand see: (a) M. Dakkach,
M. I. Lopez, I. Romero, M. Rodriguez, A. Atlamsani, T. Parella,
X. Fontrodona and A. Llobet, Inorg. Chem., 2010, 49, 7072;
(b) D. Pucci, I. Aiello, A. Aprea, A. Bellusci, A. Crispini and
20 For some selected, relatively recent examples of other routes to 1,3-
diphenylpyrazole see (a) R. S. Foster, H. Jakobi and J. P. A. Harrity,
Tetrahedron Lett., 2011, 52, 1506; (b) E. Arbaclauskiene,
G. Vilkauskaite, G. A. Eller, W. Holzer and A. Sackus, Tetrahedron,
2009, 65, 7817; (c) S. Peruncheralathan, T. A. Khan, H. Ila and
H. Junjappa, J. Org. Chem., 2005, 70, 10030; (d) A. Padwa and
T. Stengel, Archivoc, 2005, 21; (e) M. Tiecco, L. Testaferri, F. Marini,
L. Bagnoli, C. Santi and A. Temperini, Tetrahedron, 1997, 53, 4441;
(f) R. Aumann, B. Jasper and R. Frohlich, Organometallics, 1995,
¨
14, 2447.
21 M. C. Bagley, M. C. Lubinu and C. Mason, Synlett, 2007, 704.
c
442 Chem. Commun., 2012, 48, 440–442
This journal is The Royal Society of Chemistry 2012