Two-step synthesis of β-alkyl chalcones and their use in the synthesis of 3,5-diaryl-5-alkyl-4,5-dihydropyrazoles

Article abstract of DOI:10.1016/j.tetlet.2003.12.026

We report a simple and efficient two-step synthesis of variously substituted β-alkyl chalcones (7) from the corresponding Weinreb amide and a terminal alkyne, and that these chalcones are useful intermediates for the synthesis of medicinally interesting 3,5-diaryl-5-alkyl-4,5-dihydropyrazoles (6). The current methodology allows for the incorporation of many substitution patterns not available from the few previously reported approaches to compounds in this class.

Full text of DOI:10.1016/j.tetlet.2003.12.026

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1489–1493
Two-step synthesis of b-alkyl chalcones and their use in the
synthesis of 3,5-diaryl-5-alkyl-4,5-dihydropyrazoles
Christopher D. Cox,* Michael J. Breslin and Brenda J. Mariano
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Received 17 November 2003; revised 3 December 2003; accepted 5 December 2003
Abstract—We report a simple and efficient two-step synthesis of variously substituted b-alkyl chalcones (7) from the corresponding
Weinreb amide and a terminal alkyne, and that these chalcones are useful intermediates for the synthesis of medicinally interesting
3,5-diaryl-5-alkyl-4,5-dihydropyrazoles (6). The current methodology allows for the incorporation of many substitution patterns not
available from the few previously reported approaches to compounds in this class.
ꢀ 2003Elsevier Ltd. All rights reserved.
Heterocyclic rings have played an important role in
medicinal chemistry, serving as key templates central to
the development of numerous important therapeutic
agents. Among the many five-membered heterocycles
studied, 3,5-diaryl-4,5-dihydropyrazoles (1) have been
identified as active core structures in anti-bacterial,1
hypotensive,2 and anti-inflammatory3 agents, as well as
in neurotoxicity inhibitors.4 Synthetically, these mole-
cules are readily accessible through the addition of a
hydrazine to a chalcone (3), which in turn is easily
prepared by either acid- or base-catalyzed condensation
of an acetophenone with an aromatic aldehyde (Scheme
1). The fact that large combinatorial libraries have been
based upon this methodology testifies to its robustness
and wide applicability.5
During the course of a medicinal chemistry effort, we
became interested in accessing the corresponding 3,5-
diaryl-5-alkyl analogs 6, R2 ¼ alkyl. A search of the lit-
erature revealed that there is no general and convenient
synthetic method to access these valuable structures;6
however, addition of a hydrazine to a b-alkyl chalcone
(7, R2 ¼ alkyl) could provide a direct and synthetically
useful route to these targets (Scheme 2).7
Simple b-methyl chalcones with identical substitution
patterns on both aromatic rings are readily available by
self-condensation of an acetophenone.8 On the other
hand, non-symmetrical b-methyl chalcones, or chal-
cones with a different group at the b-position, prove
more problematic synthetically.9 Historically, complex
b-alkyl chalcones have been made in various ways: (1)
conjugate addition of a cuprate to a b-unsubstituted
chalcone, trapping the resultant enolate with selenium,
oxidation to the selenoxide, followed by elimination to
the chalcone;10 (2) conjugate addition of cyanide to a
O
Ar
NH2NHR1
H
2
Ar
N
Ar'
N
Ar'
3
R1
1
O
Ar
NH2NHR1
O
O
R2
Ar'
2
+
Ar
Ar
CH3
N
Ar'
H
N
R1
4
5
R2
Ar'
6
7
Scheme 1. Retrosynthesis of 3,5-diaryl-4,5-dihydropyrazoles.
O
Ar'2CuLi
+
Ar
R2
9
Keywords: Alkyl chalcone; Dihydropyrazole; Cyclization; Aryl cuprate
addition; Propargylic ketone.
8
Scheme 2. Proposed retrosynthesis of 3,5-diaryl-5-alkyl-4,5-dihydro-
pyrazoles.
* Corresponding author. Tel.: +1-215-652-2411; fax: +1-215-652-7310;
e-mail: chris_cox@merck.com
0040-4039/$ - see front matter ꢀ 2003Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.026

1490
C. D. Cox et al. / Tetrahedron Letters 45 (2004) 1489–1493
Table 1. Preparation of b-alkyl chalconesa
O
O
1. nBuLi, H
R2
THF, -78oC to rt
O
N
Me
(1)
R3
Me
2. Ar'Li, CuBr-DMS,
THF, -78oC
R1
R2
R1
11
10
Entry
R1
R2
R3
Yield (%)
a
b
c
H
H
H
Br
H
Me
H
91b
74
(CH2)3OTBS
CH2OTHP
(CH2)2OTHP
(CH2)2Ph
H
H
83
81
56c
d
e
H
OTBS
a Abbreviations: THP ¼ tetrahydropyranyl; TBS ¼ tert-butyldimethylsilyl; yields are reported for isolated, pure compounds. The products are
mixtures of (E) and (Z) isomers; see text for discussion.
b This compound was made by the addition of 1-propynylmagnesium bromide to the Weinreb amide in the first step of the sequence.
c The low yield in this transformation reflects difficulty in isolation of the pure material.
b-unsubstituted chalcone, selective alkylation at the
b-position, and elimination of cyanide;9 (3) conjugate
addition of an organozinc and copper reagent to a (2-
propynylidene)morpholinium triflate, followed by
hydrolysis;11 and (4) palladium(0)-catalyzed coupling of
b-tributylstannyl chalcones with benzyl or aryl halides.12
These methods all suffer from limitations due to the
handling of toxic compounds, limited substrate scope,
and/or long synthetic routes, making such procedures
cumbersome when a large number of derivatives are
required for studying structure–activity relationships
(SAR) against biological targets.
halide, to provide the desired b-alkyl chalcones in good
overall yield.
Utilizing this methodology, the simple b-methyl chal-
cone 11a is available in high yield, as are the b-func-
tionalized derivatives in entries b and c of Table 1.15 The
protected alcohol moiety of various chain length present
in these analogs serves as a convenient handle for the
introduction of functionality in the side chain following
cyclization to the dihydropyrazole nucleus (vide infra).
As illustrated in entry d, halides can be easily incorpo-
rated in the western aryl portion, allowing for further
diversity, if desired, via transition metal-mediated
chemistry. Finally, functionalized eastern aryl rings can
be incorporated, provided that the substituents are sta-
ble to the metalation conditions employed (entry e). It
should be noted that chalcones 11 in Table 1 are formed
as mixtures of double bond isomers in a ratio that varied
between 1:1 and 2:1. Although these isomers were sep-
arable, they were not routinely isolated since both con-
verge to the same product upon cyclization to the
dihydropyrazole.
A conceptually attractive approach to b-alkyl chalcones
is the addition of an arylcuprate to a propargylic ketone
(Scheme 2).13 Such a convenient and efficient route to
these targets is a crucial first step for wide application of
the proposed methodology to access structures 6
(R2 ¼ alkyl), and is also of value because chalcones
themselves have interesting biological properties worthy
of further study.14 In this communication, we report a
simple, two-step procedure for the synthesis of b-alkyl
chalcones in good yield from a Weinreb amide and a
terminal alkyne, and that these chalcones are useful
intermediates for the synthesis of variously N1-substi-
tuted 3,5-diaryl-5-alkyl-4,5-dihydropyrazoles (6).
We next investigated the potential of b-alkyl chalcones
in the synthesis of dihydropyrazoles. To this end, we
found that hydrazine hydrate smoothly adds to these
chalcones within 30 min in EtOH at 150 ꢁC under
microwave irradiation (Eq. 2).16 Microwave heating is
not a requirement for these reactions, as refluxing
overnight in EtOH provided similar results; however,
the shorter reaction times and the ability to easily per-
form multiple reactions in parallel with an automated
handling system make the microwave route a more
attractive option for the synthesis of moderately sized
libraries.
Our first task in this endeavor was to develop a short
and efficient synthesis of the necessary b-alkyl chalcones.
In doing so, we required that the methodology be
amenable to various substitution patterns on both aryl
rings, as well as allowing for the introduction of func-
tionalized alkyl groups at the b-position (cf., not just
simple alkyl). In this vein, we investigated the sequence
pictured in Eq. 1. Weinreb amides, available commer-
cially or readily prepared from the acid or acid chloride,
react smoothly with the lithium anion of a terminal
alkyne to provide the propargylic ketones. Reaction of
these intermediates occurs at )78 ꢁC with the cuprate
derived from CuBrÅDMS and commercially available
phenyllithium, or an aryllithium obtained via halogen–
metal exchange from a suitably functionalized aryl
Dihydropyrazoles such as 12 without substitution at N1
have been shown to rapidly undergo ene reaction with
O2,17 and, not surprisingly, could not be purified by
either normal or reverse phase chromatography. How-
ever, following concentration of the reaction mixture
and dissolving the residue in CH2Cl2, 12 reacts effi-

C. D. Cox et al. / Tetrahedron Letters 45 (2004) 1489–1493
Table 2. Synthesis of l-acyl-3,5-diaryl-5-alkyl-4,5-dihydropyrazolesa
1491
O
Ar
Ar
see text for
conditions
R1
Ar'
NH2NH2-H2O
R1
Ar'
Ar
N
(2)
N
N
EtOH, µ-wave
N
H
R1
Ar'
150oC, 30 min.
O
R2
7
13
12
b
Entry
Ar
R1
Ar0
R2
Yield (%)
a
b
c
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
NHPh
NHEt
NMe2
86
75
70
77
(CH2)2Ph
(CH2)3OH
3-HOPh
Ph
d
NMe(cyclohexyl)
N
O
e
Ph
(CH2)3OH
Ph
76
f
4-BrPh
Ph
Ph
(CH2)2OH
Me
Me
Ph
Ph
Ph
NH2
CH2CH2CH3
Ph
65
81
79
g
h
a Yields are reported for isolated, pure compounds.
b R1 substitution in the chalcones 7d–7f is the protected from of the alcohol (7d and 7e, as the tert-butyldimethylsilyl-alcohol; 7f, as the tetrahy-
dropyranyl-alcohol). The final products 13d and 13e were made by deprotection with triethylamine trihydrofluoride in CH3CN; 13f was made by
stirring in THF/MeOH with a catalytic amount of Amberlyst 15 ion-exchange resin.
ciently with a number of electrophiles to form stable N1-
acyl dihydropyrazoles as depicted in Table 2.
hydrazine, and ethyl hydrazinoacetate cyclize to form
the desired heterocycles in satisfactory yields. Unfortu-
nately, arylhydrazines perform poorly under these con-
ditions. Analysis of the NMR spectrum of the crude
reaction of 11a with phenylhydrazine indicates that only
a small amount of desired product was formed, as evi-
denced by the diagnostic AB quartet at d 3.4 ppm
attributable to the protons at C-4 of the dihydropyra-
zole ring. When the same reaction is performed with the
more nucleophilic 4-methoxyphenylhydrazine, analysis
of the crude NMR indicates much higher conversion
(ꢀ50%); however, attempts to isolate the product were
unsuccessful. We have noted some instability toward
acidic conditions of 1-alkyl-3,5-diaryl-5-alkyl-4,5-di-
hydropyrazoles such as 14b, and this may be related to
our inability to isolate the corresponding N1-aryl
dihydropyroles following silica gel chromatography.20
Addition of aryl or alkyl isocyanates to 12 provides the
desired N1-urea dihydropyrazoles 13a and 13b in good
yield. Surprisingly, attempts to reach N,N-dimethyl urea
13c by acylation of 12 with dimethylcarbamoyl chloride
were unsuccessful, resulting in no reaction. After some
experimentation, we found that 12 reacts with triphos-
gene to form the putative carbamoyl chloride, which can
be treated with symmetrical, non-symmetrical, and cyclic
amines (entries c, d, and e), as well as ammonia (entry f)
to provide dihydropyrazoles 13 in good yields.18 In
contrast to the case with carbamoyl chlorides, 12 does
react with acyl chlorides such as butyryl chloride and
benzoyl chloride to provide 13g and 13h, respectively. All
attempts to sulfonylate 12 were unsuccessful. The alco-
hol functionality in the side chain of dihydropyrazoles
13d–f can be converted to a number of other important
functional groups such as aldehyde, acid, amine, and
ether for additional diversity.19
In conclusion, we have disclosed a simple, two-step
procedure for the synthesis of diverse b-alkyl chalcones
from the Weinreb amide and a terminal alkyne, and that
these chalcones are useful intermediates for the synthesis
of 3,5-diaryl-5-alkyl-4,5-dihydropyrazoles with various
substitution patterns at N1. In a forthcoming paper, we
will demonstrate how this versatile methodology
allowed us to pursue a fruitful medicinal chemistry effort
within this structural class.
To further explore the potential of b-alkyl chalcones in
the synthesis of 3,5-diaryl-5-alkyl-4,5-dihydropyrazoles,
we examined N1 alkyl and aryl substitution as illus-
trated in Eq. 3. By increasing the reaction time to 45 min
and adding a catalytic amount of acetic acid, methyl-
O
Ph
NH2NHR, EtOH, cat. HOAc
Me
Ph
Ph
Me
(3)
N
µ-wave, 150oC, 45 min
N
R
Acknowledgements
Ph
11a
We thank Dr. Charles Ross and Ms. Joan Murphy for
performing the high resolution mass spectral analyses,
and Dr. Steven M. Pitzenberger for 1D NOE analysis.
14a R = Me, 51%
14b R = CH2CO2Et, 70%
14c R = Ph, ~ 10% (not isolated)

1492
C. D. Cox et al. / Tetrahedron Letters 45 (2004) 1489–1493
25 min to provide 6.3g (20.9 mmol, 87%) of the propar-
References and notes
gylic ketone as a pale yellow oil. To a suspension of 2.2 g
(10.7 mmol) of CuBrÅDMS in 30 mL of THF at )78 ꢁC
was added 10.7 mL (21.4 mmol) of a 2.0 M solution of
PhLi in dibutylether. After stirring for 1.5 h, 2.7 g
(8.9 mmol) of the above-prepared ketone in 5 mL of
THF was added, and the mixture was allowed to stir for
an additional 3h at )78 ꢁC, and warmed to 0 ꢁC for
15 min before being quenched with saturated aqueous
NH4Cl. The mixture was partitioned with EtOAc, the
layers were separated, the aqueous layer was extracted
with 2 · EtOAc, the organic layers were combined, washed
with brine, dried over Na2SO4, and concentrated. The
crude material was loaded onto a 40 g silica gel cartridge
and eluted with a gradient of 0–25% EtOAc in hexanes to
provide 2.89 g (7.6 mmol, 85%) of 11b as a yellow oil;
NMR analysis indicated that there was a 1.1:1 mixture of
E:Z isomers. Careful separation of a fraction of this
material provided the pure isomers, whose identities were
determined by 1D NOE analysis. Data for 11b-(E) (first to
elute): 1H NMR (500 MHz, CDCl3) d 8.0 (m, 2H), 7.6–7.4
(m, 8H), 7.1 (s, 1H), 3.7 (t, J ¼ 6:3Hz, 2H), 3.1 (m, 2H),
1.75 (m, 2H), 0.9 (s, 9H), 0.01 (s, 6H) ppm. Data for 11b-
1. (a) Sachchar, S. P.; Singh, A. K. J. Indian Chem. Soc.
1985, 62, 142–146; (b) Havaldar, F. H.; Fernandes, P. S. J.
Indian Chem. Soc. 1988, 65, 691–694; (c) Cihat, C.;
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Tayhan, A.; Sarac, S.; Yulug, N. J. Indian Chem. Soc.
1990, 67, 571–574.
2. Turan-Zitouni, G.; Chevallet, P.; Kilic, F. S.; Erol, K. Eur.
J. Med. Chem. 2000, 35, 635–641.
3. Satti, N. K.; Suri, K. A.; Suri, O. P. Indian Drugs 1987, 24,
492–493.
4. Shshikura, J.; Inami, H.; Kaku, H.; Yamahita, H.; Ohno,
K.; Tsutsumi, R. PCT WO 01/32173 A1, 2001.
5. (a) Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. J.;
Troth, J. R.; Coffen, D. L. Tetrahedron 1998, 54, 4085–
4096; (b) Bauer, U.; Egner, B. J.; Nilsson, I.; Berghult, M.
Tetrahedron Lett. 2000, 41, 2713–2717.
6. Although there are reports in the literature of compounds
in this class, they are very limited in terms of the
substitution patterns available by the reported methodol-
ogy; see: (a) Harris, D. J.; Kan, G. Y.-P.; Tschamber, T.;
Snieckus, V. Can. J. Chem. 1980, 58, 494–500; (b)
Matsumura, N.; Kunugihara, A.; Yoneda, S. Tetrahedron
1
(Z) (second to elute): H NMR (500 MHz, CDCl3) d 7.8
ꢁ
Lett. 1984, 25, 4529–4532; (c) Molina, P.; Tarrage, A.;
(m, 2H) 7.45 (m, 1H), 7.35 (m, 2H), 7.25–7.1 (m, 5H), 6.7
(s, 1H), 3.65 (t, J ¼ 6:3Hz, 2H), 2.65 (t, J ¼ 7:6 Hz, 2H),
1.7 (m, 2H), 0.9 (s, 9H), 0.05 (s, 6H) ppm. Data for 11b:
HRMS (ES) calcd M+H for C24H32O2Si: 381.2245.
Found: 381.2251.
Serrano, C. Tetrahedron 1984, 40, 4901–4910; (d) Jain, R.;
Sponsler, M. B.; Coms, F. D.; Dougherty, D. A. J. Am.
Chem. Soc. 1988, 110, 1356–1366.
7. This addition has been reported; see: (a) El-Sharief, A. M.;
Ammar, Y. A.; Mohamed, Y. A.; Zaki, M. E. A. J. Indian
Chem. Soc. 1984, 61, 537–543; (b) Morkovnik, A. S.;
Okhlobystin, O. Chem. Heterocycl. Chem. (Engl. Transl.)
1985, 21, 461–464.
16. This stands in contrast to the simple b-unsubstituted
chalcones, which react completely within 5 min under
these conditions, or in 1–2 h in refluxing CH2Cl2.
17. Baumstark, A. L.; Dotrong, M.; Vasquez, P. C. Tetra-
hedron Lett. 1987, 28, 1963–1966.
8. Wayne, W.; Adkins, H. In Organic Syntheses; Wiley: New
York, 1955; Collect. Vol. 3, pp 367–369.
18. General procedure for cyclization/acylation of b-alkyl
9. Nielsen, S. F.; Kharazmi, A.; Christensen, S. B. Bioorg.
Med. Chem. Lett. 1998, 6, 937–945, and references cited
therein.
chalcones:
5-[2-(3-hydroxyphenyl)ethyl]-N,N-dimethyl-
3,5-diphenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
(13c). To a solution of 282 mg (0.64 mmol) of 11e in 3mL
of EtOH was added 62 lL (1.27 mmol) of hydrazine
hydrate. The reaction was heated in the microwave for
30 min at 150 ꢁC, cooled to room temperature, and
concentrated by rotary evaporation. The residue was
dissolved in 20 mL of THF, 180 lL (1.27 mmol) of
triethylamine was added, followed by 94.5 mg (0.32 mmol)
of triphosgene. After stirring for 7 h, 3.2 mL (6.4 mmol) of
a 2 M solution of dimethylamine in THF was added, and
stirring was continued overnight. The reaction was trans-
ferred to a separatory funnel with 10% aqueous citric acid
and EtOAc, the layers were separated, the organic layer
was washed with brine, dried over Na2SO4, and concen-
trated. The residue was dissolved in 15 mL of anhydrous
CH3CN and 1.5 mL of triethylamine trihydrofluoride was
added, and the mixture was stirred for 24 h. The reaction
was then partitioned between saturated aqueous NaHCO3
and EtOAc, the layers were separated, the organic layer
was washed with brine, dried over Na2SO4, and concen-
trated by rotary evaporation. The residue was purified on
a 12 g silica gel cartridge with a gradient of 10–100%
EtOAc in hexanes over 15 min to provide 185 mg
(0.45 mmol, 70%) of 13c as a white solid. Data for 13c:
1H NMR (500 MHz, CDCl3) d 7.65 (m, 2H), 7.4 (m, 3H),
7.3–7.1 (m, 6H), 7.05 (m, 1H), 6.75 (m, 1H), 6.7 (s, 1H),
6.45 (m, 1H), 3.35 (q, 2H), 3.25–3.15 (m, 1H), 3.1 (s, 6H),
2.7–2.6 (m, 1H), 2.5 (m, 1H), 2.3(m, 1H) ppm. HRMS
(APCI) calcd M+H for C26H27N3O2: 414.2176. Found:
414.2165.
10. Pelter, A.; Ward, R. S.; Ohlendorf, D.; Ashdown, D. H. J.
Tetrahedron 1979, 35, 531–533.
11. Brunner, M.; Maas, G. Synthesis 1995, 957–963.
12. Takeda, T.; Kabasawa, Y.; Fujiwara, T. Tetrahedron
1995, 51, 2515–2524.
13. A search of the Beilstein CrossFire Database only
identified several examples of the formation of a b-alkyl
chalcone from a propargylic ketone. In all cases, it
involved the addition of an alkyl nucleophile to a diaryl
propargylic ketone: (a) Kohler, E. P.; Barrett, G. R. J.
Am. Chem. Soc. 1924, 46, 747–753; (b) Fouli, F. A.;
Basyouni, M. N. Acta Chim. Acad. Sci. Hung. 1981, 106,
297–302; (c) Ref. 11.
14. (a) Ref. 9; (b) Kidwai, M.; Misra, P. Synth. Commun.
1999, 29, 3237–3250; (c) Potter, G. A.; Butler, P. C.;
Wanogho, E. PCT WO 2001/072680, 2001.
15. General procedure for the synthesis of b-alkyl chalcones:
6-{[tert-butyl(dimethyl)silyl]oxy}-1,3-diphenylhex-2-en-1-
one(11b). To a solution of 5.0 g (25.4 mmol) of tert-
butyldimethyl-pent-4-ynyloxy-silane (Koseki, Y.; Sato,
H.; Watanabe, Y.; Nagasaka, T. Org. Lett. 2002, 4,
885–888) in 100 mL of THF at )78 ꢁC under an atmo-
sphere of N2 was added dropwise 10.2 mL (25.4 mmol) of
2.5 M nBuLi in hexane. After stirring for 1 h at that
temperature, 4.0 g (24.2 mmol) of N-methoxy-N-methyl
benzamide in 20 mL of THF was added, the cooling bath
was removed, and stirring was continued for 3h at room
temperature. The reaction was quenched with saturated
aqueous NH4Cl, extracted with 2 · EtOAc, washed with
brine, dried over Na2SO4, and concentrated. The crude
material was loaded onto a 40 g silica gel cartridge and
eluted with a gradient of 0–55% EtOAc in hexanes over
19. In a series of closely related analogs, we found that the
dihydropyrazole core is stable to oxidative (Dess–Martin
Periodinane, cat. CrO3/H5IO6), reductive [LiBH4,

C. D. Cox et al. / Tetrahedron Letters 45 (2004) 1489–1493
1493
Na(OAc)3BH] alkylative (NaH, DMF, RX), and nucleo-
philic (NaN3, DMF, 80 ꢁC) conditions.
20. A major product from the acid-promoted decomposi-
tion of N1-alkyl-3,5-diaryl-5-alkyl-4,5-dihydropyrazoles
appears to be the product of a two electron oxidation,
implicating the formation of the corresponding pyr-
role; however, due to disubstitution at C5, this could
only occur via rearrangement. similar rearrange-
ment has been noted in 1-sulfonyl-3,5-diaryl-5-alkyl-
4,5-dihydropyrazoles under basic conditions; see: Lem-
pert-Sreter, M.; Lempert, K. Tetrahedron 1975, 31,
1677–1682.
A