Gold-catalyzed three-component annulation: Efficient synthesis of highly functionalized dihydropyrazoles from alkynes, hydrazines, and aldehydes or ketones

Article abstract of DOI:10.1021/ol203072u

Polysubstituted dihydropyrazoles were directly obtained by a gold-catalyzed three-component annulation. This reaction consists of a Mannich-type coupling of alkynes with N,N′-disubstituted hydrazines and aldehydes/ketones followed by intramolecular hydroa

Full text of DOI:10.1021/ol203072u

ORGANIC
LETTERS
2012
Vol. 14, No. 1
326–329
Gold-Catalyzed Three-Component
Annulation: Efficient Synthesis of Highly
Functionalized Dihydropyrazoles from
Alkynes, Hydrazines, and Aldehydes or
Ketones
Yamato Suzuki, Saori Naoe, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku,
Kyoto 606-8501, Japan
nfujii@pharm.kyoto-u.ac.jp; hohno@pharm.kyoto-u.ac.jp
Received November 15, 2011
ABSTRACT
Polysubstituted dihydropyrazoles were directly obtained by a gold-catalyzed three-component annulation. This reaction consists of a Mannich-type
coupling of alkynes with N,N0-disubstituted hydrazines and aldehydes/ketones followed by intramolecular hydroamination. Cascade cyclization
using 1,2-dialkynylbenzene derivatives as the alkyne component was also performed producing fused tricyclic dihydropyrazoles in good yields.
The development of efficient, direct and environmen-
tally friendly processes has recently garnered much inter-
est in the field of synthetic chemistry. The multicom-
ponent reaction (MCR) is one of the most attractive
approaches to achieve this aim, which enables direct
construction of the desired molecules having an increased
structural complexity from a set of small and simple
starting materials.1 MCRs allow diversity-oriented synth-
esis of the target compounds by simply changing the
substituent(s) of each reaction component. Particularly,
ring construction using MCR (multicomponent annula-
tion) is a powerful strategy for facile preparation of
diverse polysubstituted cyclic compounds. A transition-
metal-catalyzed Mannich-type three-component coupling
of alkynes, aldehydes, and amines (A3 coupling) (eq 1)2,3 is
an attractive reaction not only for facile preparation of
propargylamines but also as an elementary reaction for a
cascade process. Our group4 and others5 have recently
(3) Catalytic Mannich-type coupling reactions of terminal reactions
alkynes with isolated nitrones or imines have been also reported. For
€
examples, see: (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem.
Soc. 1999,121, 11245–11246. (b) Fischer, C.; Carreira, E. M. Org. Lett. 2001,
3, 4319–4321. (c) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497–1499.
(4) (a) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed.
2007, 46, 2295–2298. (b) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno,
H. Org. Lett. 2008, 10, 3535–3838. (c) Ohta, Y.; Oishi, S.; Fujii, N.;
Ohno, H. Chem. Commun. 2008, 835–837. (d) Suzuki, Y.; Ohta, Y.;
Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 4246–4251. (e)
Ohta, Y.; Kubota, Y.; Watabe, T.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2009, 74, 6299–6302. (f) Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H.
Org. Lett. 2009, 11, 1979–1982. (g) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii,
N.; Ohno, H. J. Org. Chem. 2009, 74, 7052–7058.
(5) (a) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323–4326. (b) Yoo, W.-J.;
Li, C.-J. Adv. Synth. Catal. 2008, 350, 1503–1506. (c) Zhang, Q.; Cheng,
M.; Hu, X.; Li, B.-G.; Ji, J.-X. J. Am. Chem. Soc. 2010, 132, 7256–7257.
(d) Campbell, M. J.; Toste, F. D. Chem. Sci. 2011, 2, 1369–1378. For
Rh/Cu-catalyzed double A3-coupling and [2 þ 2 þ 2] cycloaddition
cascade, see: (e) Bonfield, E. R.; Li, C.-J. Adv. Synth. Catal. 2008, 350,
370–374.
€
(1) For recent reviews, see: (a) D’Souza, D. M.; Muller, T. J. J. Chem.
Soc. Rev. 2007, 36, 1095–1108. (b) Ganem, B. Acc. Chem. Res. 2009, 42,
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463–472. (c) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486.
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r
10.1021/ol203072u
Published on Web 12/16/2011
2011 American Chemical Society

reported transition-metal-catalyzed cascade reactions in-
cluding an A3 coupling and the subsequent nucleophilic
cyclization onto an alkyne moiety, leading to heterocyclic
compounds. However, to the best of our knowledge, there
have been no reports of three-component annulation in
which all the reaction components of A3 coupling are
incorporated in the newly formed ring.
dihydropyrazoles 5 (Scheme 1). This annulation consists
of the novel catalytic A3 coupling using hydrazine deri-
vatives and 5-endo-dig intramolecular hydroamination of
the resulting propargyl hydrazine 4. Both reactions are
desirably promoted by the same gold catalyst.9,10 We
expected that the regioselectivity can be controlled by
differentiation of the electron density of the two nitrogen
atoms of the hydrazines. These two nucleophilic groups
can serve as the first hydrazonium construction11 and
the consecutive cyclization separately by using two dis-
tinctive accessory groups (R4 and R5). By utilizing the
enamine structure of the resulting dihydropyrazoles
5, further gold-catalyzed nucleophilic cyclization might
produce fused pyrazole derivatives when using alkyne
components bearing an additional functionality. Herein
we describe a gold-catalyzed annulation12,13 of alkynes,
hydrazines,14 and aldehydes/ketones for diversity-oriented
and regioselective synthesis of pyrazole derivatives. The
only waste product of the reaction would be water. Direct
synthesis of fused tricyclic compounds 6 via a gold-
catalyzed cascade cyclization using 1,2-dialkynylbenzene
derivatives as the alkyne component is also described.15
Initial investigations focused on the search for suitable
catalysts and solvents for the three-component annula-
tion of phenylacetylene (1a), isobutyraldehyde (2a), and
hydrazine derivative 3a (Table 1). The screening of various
Scheme 1. Gold-Catalyzed Three-Component Annulation
(9) For gold-catalyzed Mannich-type reactions of terminal alkynes,
see: (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584–9585. (b) Lo,
V. K.-Y.; Kung, K. K.-Y.; Wong, M.-K.; Che, C.-M. J. Organomet.
Chem. 2009, 694, 583–591. (c) Graf, T. A.; Anderson, T. K.; Bowden,
N. B. Adv. Synth. Catal. 2011, 353, 1033–1038. (d) Cheng, M.; Zhang,
Q.; Hu, X.-Y.; Li, B.-G.; Ji, J.-X.; Chan, A. S. C. Adv. Synth. Catal. 2011,
353, 1274–1278. For a review, see: (e) Skouta, R.; Li, C.-J. Tetrahedron
2008, 64, 4917–4938.
Pyrazole derivatives are well recognized as an impor-
tant class of heterocyclic compounds which exhibit a
variety of biological activities.6 Although a number of
approaches to pyrazole derivatives have been developed,7
they sometimes, especially for polysubstituted ones, suf-
fer from the need for preparation via multistep processes,
a limited scope of substituents, and/or regioselectivity in
the substitution of two adjacent nitrogen atoms. Hence,
development of the multicomponent annulation metho-
dology that provides an efficient and diversity-oriented
route to pyrazole derivatives would facilitate the identi-
fication of pyrazole-based biologically active molecules.8
For this purpose, we designed a novel gold-catalyzed
three-component annulation of alkynes 1, aldehydes/
ketones 2, and hydrazines 3 yielding highly functionalized
(10) The silver-catalyzed cyclizationa or iodocyclizationb of propar-
gylhydrazine derivatives have been reported recently, see: (a) Lee, Y. T.;
Chung, Y. K. J. Org. Chem. 2008, 73, 4698–4701. (b) Okitsu, T.; Sato,
K.; Wada, A. Org. Lett. 2010, 12, 3506–3509.
(11) Quite recently, Hashmi et al. have reported related iminium-type
intermediates (4,5-dihydrooxazoliums) and the nucleophilic attack to
these intermediates in gold-catalyzed reactions; see: Hashmi, A. S. K.;
Molinari, L.; Rominger, F.; Oeser, T. Eur. J. Org. Chem. 2011, 2256–
2264.
(12) Zhang et al. have reported a gold-catalyzed [2 þ 2 þ 1] annula-
tion of terminal alkynes, nitriles, and an oxygen atom derived from an
oxidant yielding 2,5-disubstituted oxazoles; see: He, W.; Li, C.; Zhang,
L. J. Am. Chem. Soc. 2011, 133, 8482–8485.
(13) For reviews on the gold-catalyzed synthesis of heterocycles, see:
€
(a) Hashmi, A. S. K.; Buhrle, M. Aldrichimica Acta 2010, 43, 27–33. (b)
Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536–6544.
(14) For the use of hydrazines in gold-catalyzed conversions, see: (a)
€
€
Hashmi, A. S. K.; Buhrle, M.; Wolfle, M.; Rudolph, M.; Wieteck, M.;
Rominger, F.; Frey, W. Chem.;Eur. J. 2010, 16, 9846–9854. (b) Patil,
N. T.; Konala, A. Eur. J. Org. Chem. 2010, 6831–6839. (c) Kinjo, R.;
Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2011, 50, 5560–
5563. Very recently, He et al. have reported gold-catalyzed synthesis of
dihydropyrazoles using alkynes and diaziridines; see: Capretto, D. A.;
Brouwer, C.; Poor, C. B.; He, C. Org. Lett. 2011, 13, 5842–5845.
(15) Recently, our group has reported a gold-catalyzed cascade
cyclization using diyne derivatives; see: (a) Hirano, K.; Inaba, Y.;
Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Adv. Synth. Catal. 2010,
352, 368–372. (b) Hirano, K.; Inaba, Y.; Takahashi, N.; Shimano, M.;
Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 1212–1227. See
also: (c) Hirano, K.; Inaba, Y.; Takasu, K.; Oishi, S.; Takemoto, Y.;
Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 9068–9080. Hashimi et al.
have also reported gold-catalyzed cascade reactions using ene-(di)yne
compounds; see: (d) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org.
Lett. 2001, 3, 3769–3771. (e) Hashmi, A. S. K.; Grundl, L. Tetrahedron
(6) For examples, see: (a) Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis,
P. Bioorg. Med. Chem. Lett. 1996, 6, 1819–1824. (b) Penning, T. D.;
Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers,
R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn,
J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40,
1347–1365. (c) Yabanoglu, S.; Ucar, G.; Gokhan, N.; Salgin, U.;
Yesilada, A.; Bilgin, A. J. Neural. Transm. 2007, 114, 769–773. (d)
Donohue, S. R.; Dannals, R. F.; Halldin, C.; Pike, V. W. J. Med. Chem.
2011, 54, 2961–2970.
ꢀ
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(7) For a recent review, see: Fustero, S.; Sanchez-Rosello, M.; Barrio,
ꢀ
P.; Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984–7034.
(8) For multicomponent syntheses of pyrazole derivatives, see: (a)
Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487–
4489. (b) Liu, H.-L.; Jiang, H.-F.; Zhang, M.; Yao, W.-J.; Zhu, Q.-H.;
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Tang, Z. Tetrahedron Lett. 2008, 49, 3805–3809. (c) Willy, B.; Muller,
2005, 61, 6231–6236. (f) Hashmi, A. S. K.; Haffner, T.; Rudolph, M.;
T. J. J. Org. Lett. 2011, 13, 2082–2085.
Rominger, F. Chem.;Eur. J. 2011, 17, 8195–8201.
Org. Lett., Vol. 14, No. 1, 2012
327

while the use of AgOTf or Ph3PAuCl alone proved un-
successful (entries 3 and 5). The phosphine ligand is
important for both the A3 coupling and cyclization
(entry 8). It is noteworthy that the reaction performed at
room temperature led to formation of the propargyl
hydrazine 4a (entry 7), which strongly supports the reac-
tion mechanism shown in Scheme 1.16 The solvent screen-
ing (entries 9ꢀ13) revealed that acetic acid or 1,2-di-
chloroethane (1,2-DCE) improved the reaction rate and
provided high yields even with a decreased loading of the
catalyst (entries 11ꢀ13). Finally, the most efficient con-
version was observed when using an N-heterocyclic car-
bene (NHC) ligand IPr [IPr = 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene] in 1,2-DCE (entry 15) instead
of triphenylphosphine.
Table 1. Optimization of Reaction Conditionsa
catalyst
(mol %)
T
time
(h)
yield
(%)b,c
entry
solvent
(°C)
1
2
3
4
5
6
CuBr (5)
toluene
toluene
toluene
toluene
toluene
toluene
50
50
50
50
50
50
18
18
18
20
12
2
0 (31)
Cu(OTf)2 (5)
AgOTf (5)
AuBr3 (5)
Ph3PAuCl (5)
Ph3PAuCl/
AgOTf (5)
Ph3PAuCl/
AgOTf (5)
AuCl/
0 (trace)
6 (45)
0 (trace)
0
83
7
toluene
toluene
MeCN
EtOH
rt
3
12
2
trace (42)
8
50
50
50
50
50
50
50
50
11 (14)
72
AgOTf (5)
Ph3PAuCl/
AgOTf (5)
Ph3PAuCl/
AgOTf (5)
Ph3PAuCl/
AgOTf (5)
Ph3PAuCl/
AgOTf (2)
Ph3PAuCl/
AgOTf (2)
IPrAuCl/
9
10
11
12
13
14
15
4
73
AcOH
1
88
AcOH
3
87
1,2-DCE
AcOH
1.5
3
85
85
AgOTf (2)
IPrAuCl/
AgOTf (2)
1,2-DCE
1
96
a The reaction was carried out with 3a (0.18 mmol), 1a (1.2 equiv),
and 2a (1.2 equiv). b Isolated yields. c Yields in parentheses show those
of propargylamine 4a.
alkynophilic transition metal catalysts was performed at
50 °C in toluene. The reaction with CuBr, a widely used
catalyst for A3-coupling,2,4,5d afforded the propargyl hy-
drazine 4a in 31% yield without producing the annulation
product 5a (entry 1). Contrary to our expectation, AuBr3,
reported as an efficient catalyst for A3-coupling,5c,9
showed almost no activity toward A3-coupling using hy-
drazine 3a as the amine component, yielding only a trace
amount of 4a (entry 4). On the other hand, use of 5 mol %
of Ph3PAuCl/AgOTf resulted in efficient conversion to
give a good yield of dihydropyrazole 5a (83%, entry 6),
(16) Other pathways producing the propargyl hydrazine 4, for ex-
ample, initial formation of a propargyl alcohol from an alkyne 1 and a
carbonyl compound 2 followed by substitution at the propargylic
position, are also conceivable. However, the following observation
would support our proposed mechanism shown in Scheme 1: the two-
component reaction of phenylacetylene 1a and isobutyraldehyde 2a
under the optimized conditions (Table 1, entry 15) afforded multi-
products containing a small amount of the propargyl alcohol. Unfortu-
nately, for synthesis of 5m (Figure 1), premixing of a hydrazine and a
ketone in 1,2-DCE at 50 °C for 1 h before addition of the catalysts and
phenylacetylene had no effect on the yield, presumably due to the
reversible nature of the iminium formation.
Figure 1. Evaluation of Reaction Scope.a,b
Having established the effective reaction conditions for
the three-component annulation, we evaluated the reac-
tion scope using other alkynes, hydrazines, and aldehydes/
ketones (Figure 1). For terminal alkynes, a range of sub-
stituents (R1) were tolerated including benzene rings
bearing an electron-withdrawing or -donating group
328
Org. Lett., Vol. 14, No. 1, 2012

(5b and 5c; 81% and 90%, respectively) and a bulky alkyl
group (5d; 79%), although 1-hexyne afforded an insepara-
ble mixture of the dihydropyrazole 5e and its regioisomer
5e0 (3:1; 85% combined yield).17 The use of hydrazine
bearing a phenyl group as R4 instead of a benzyl group was
also successful (5f; 84%). Similarly, other aliphatic or
aromatic aldehydes gave the desired annulation products
(5gꢀj) under the slightly modified reaction conditions in
some cases: for aromatic aldehydes, acetic acid was the
solvent of choice to obtain better yields of 5. It is worth
noting that ketones can be used in this reaction if an
increased amount of the catalyst (5 mol %) was utilized.18
Using cyclopentanone or cyclohexanone, spirocyclic dihy-
dropyrazoles 5k and 5l were obtained in good yields (78%
and 88%, respectively). Furthermore, an acyclic ketone
was also suitable for the reaction to give 5m albeit in
modest yield (47%). In addition, we expected these reac-
tion conditions to be applicable for the synthesis of 2,3,5-
trisubstituted dihydroisoxazoles by using hydroxylamine
derivatives instead of hydrazines. In this reaction, the
nitrones generated from aldehydes and hydroxylamines
might play the same role as the hydrazonium cation.3a How-
ever, the reaction using phenylacetylene (1a), isobutyral-
dehyde (2a), and PMBNHOH (PMB = 4-methoxybenzyl)
(7) gave the desired dihydroisoxazole 8 in only low yield. In
contrast, by using the isolated nitrone (prepared from 2a
and 7) and diisopropylethylamine (DIPEA) as an additive,
8 was obtained in moderate yield (56%) (see Supporting
Information for details).
Scheme 2. Gold-Catalyzed Cascade Cyclizationa
a The reaction was carried out using 10, 2a (2.0 equiv), and 3 (1.2 equiv).
enamine structure of the resulting dihydropyrazoles. To
our delight, by using 1-ethynyl-2-(phenylethynyl)benzene
10a as an alkyne component, the three-component annu-
lation and subsequent cyclization proceeded smoothly to
provide the benzene-fused dihydroindazole 6a in good
yield (84%, Scheme 2). Use of the diyne 10b bearing an
alkyl group for R1 and the methyl carbamate 3b also led
to the desired tricyclic product 6b in 65% yield.
In summary, we have developed a novel gold-catalyzed
three-component annulation of alkynes, hydrazines, and
aldehydes/ketones for the direct synthesis of polysubsti-
tuted dihydropyrazoles. This reaction shows broad sub-
strate scope for each reaction component and furnished
various types of substituted products from a set of simple
and easily available starting materials. Use of 1,2-diethy-
nylbenzene derivatives as the alkyne component produces
fused tricyclic compounds via the gold-catalyzed cascade
cyclization. Application of these dihydropyrazole and
fused heterocyclic scaffolds for the development of bio-
logically active molecules is underway.
This reaction provides a convenient access to tetrahy-
dropyrazoles. For example, removal of the benzyl group
from the dihydropyrazole 5a under the standard condi-
tions accompanied hydrogenation of a dihydropyrazole
ring to afford 3,5-cis-tetrahydropyrazole 9a stereoselec-
tively (eq 2).
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on Innovative Areas
“Integrated Organic Synthesis” (H.O.) and the Targeted
Proteins Research Program from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
Y.S. is grateful for ResearchFellowships from the JSPS for
Young Scientists.
Finally, we turned our attention to the domino process
through the three-component annulation, utilizing the
(17) Removal of the Boc group of the mixture of 5e and 5e0 afforded
the corresponding 4,5-dihydro-1H-pyrazole derivative as a single pro-
duct (see Supporting Information for details).
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(18) A gold-catalyzed A3-coupling using cyclic ketones has been
reported recently.9d
Org. Lett., Vol. 14, No. 1, 2012
329