Room temperature ICl-induced dehydration/iodination of 1-acyl-5-hydroxy-4, 5-dihydro-1H-pyrazoles. A selective route to substituted 1-acyl-4-iodo-1H- pyrazoles

Article abstract of DOI:10.1021/jo800789p

(Chemical Equation Presented) A number of new functionally substituted 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles have been prepared in moderate to excellent yields from the corresponding 2-alkyn-1-ones. The resulting dihydropyrazoles undergo dehydration and iodination in the presence of ICl and Li₂CO₃ at room temperature to provide 1-acyl-4-iodo-1H- pyrazoles.

Full text of DOI:10.1021/jo800789p

Room Temperature ICl-Induced Dehydration/Iodination of
1-Acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles. A Selective Route to
Substituted 1-Acyl-4-iodo-1H-pyrazoles
Jesse P. Waldo, Saurabh Mehta, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed April 10, 2008
A number of new functionally substituted 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles have been prepared
in moderate to excellent yields from the corresponding 2-alkyn-1-ones. The resulting dihydropyrazoles
undergo dehydration and iodination in the presence of ICl and Li2CO3 at room temperature to provide
1-acyl-4-iodo-1H-pyrazoles.
SCHEME 1
Introduction
Pyrazoles and derivatives have attracted considerable attention
due to the wide variety of biological activities they exhibit,
including hypoglycemic, antimicrobial, amoebicidal, antibacte-
rial, anti-inflammatory, antipyretic, and analgesic activities.1
Specifically, 5-hydroxy-4,5-dihydro-1H-pyrazoles are known to
possess anti-inflammatory and analgesic activity.2 Pyrazoles
exhibit analgesic,3 antimicrobial,4 anti-inflammatory,5 antihy-
pertensive,6 and hypoglycemic7 activities, and appear promising
as potential antiprotozoal and cytotoxic agents,8 and CB1
cannabinoid receptor antagonists as appetite suppressants for
the treatment of obesity.9 Even today, the pyrazole core con-
tinues to emerge as a central candidate for pharmaceutical and
agricultural applications.10
We recently reported the synthesis of highly substituted
isoxazoles by the electrophilic cyclization of 2-alkyn-1-one
O-methyl oximes (Scheme 1).11 The requisite ynone O-methyl
(10) (a) Elguero, J. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon-Elsevier Science: Oxford,
UK, 1996; Vol. 6, pp 1-75. (b) Sutharchanadevi, M.; Murugan, R. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon-Elsevier Science: Oxford, UK, 1996; Vol. 6, pp 221-
260. (c) Graneto, M. J.; Kurumbail, R. G.; Vazquez, M. L.; Shieh, H.-S.; Pawlitz,
J. L.; Williams, J. M.; Stallings, W. C.; Geng, L.; Naraian, A. S.; Koszyk, F. J.;
Stealey, M. A.; Xu, X. D.; Weier, R. M.; Hanson, G. J.; Mourey, R. J.; Compton,
R. P.; Mnich, S. J.; Anderson, G. D.; Monahan, J. B.; Devraj, R. J. Med. Chem.
2007, 50, 5712. (d) Diana, P.; Carbone, A.; Barraja, P.; Martorana, A.; Gia, O.;
DallaVia, L.; Cirrincione, G. Bioorg. Med. Chem. Lett. 2007, 17, 6134. (e)
Gokhan-Kelekci, N.; Yabanoglu, S.; Kupeli, E.; Salgin, U.; Ozgen, O.; Ucar,
G.; Yesilada, E.; Kendi, E.; Yesilada, A.; Bilgin, A. A. Bioorg. Med. Chem.
2007, 15, 5775. (f) Lin, R.; Chiu, G.; Yu, Y.; Connolly, P. J.; Li, S.; Lu, Y.;
Adams, M.; Fuentes-Pesquera, A. R.; Emanuel, S. L.; Greenberger, L. M. Bioorg.
Med. Chem. Lett. 2007, 17, 4557. (g) Pfefferkorn, J. A.; Choi, C.; Larsen, S. D.;
Auerbach, B.; Hutchings, R.; Park, W.; Askew, V.; Dillon, L.; Hanselman, J. C.;
Lin, Z.; Lu, G. H.; Robertson, A.; Sekerke, C.; Harris, M. S.; Pavlovsky, A.;
Bainbridge, G.; Caspers, N.; Kowala, M.; Tait, B. D. J. Med. Chem. 2008, 51,
31.
(1) Elguero, J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Pergamon Press: New York, 1984; Vol. 5, pp 291-297..
(2) de Souza, F. R.; Fighera, M. R.; Lima, T. T. F.; de Bastiani, J.; Barcellos,
I. B.; Almeida, C. E.; Oliveira, M. R.; Bonacorso, H. G.; Flores, A. E. Pharm.
Biochem. BehaVior 2001, 68, 525.
(3) Menozzi, G.; Schenone, P.; Mosti, L.; Mattioli, F. J. Heterocycl. Chem.
1993, 30, 997.
(4) Singh, S. P.; Naithani, R.; Aggarwal, R.; Prakesh, O. Indian J. Heterocycl.
Chem. 1992, 11, 27.
(5) Nargund, L. V. G.; Hariprasad, V.; Reddy, G. R. N. J. Pharm. Sci. 1992,
81, 892.
(6) Ashton, W. T.; Hutchins, S. M.; Greenlee, W. J.; Doss, G. A.; Chang,
R. S. L.; Lotti, V. J.; Faust, K. A.; Chen, T. B.; Zingaro, G. J.; Kivlighn, S. D.;
Siegl, P. K. S. J. Med. Chem. 1993, 36, 3595.
(7) Bauer, V. J.; Dalalian, H. P.; Fanshawe, W. J.; Safir, S. R.; Tocus, E. C.;
Boshart, C. R. J. Med. Chem. 1968, 11, 981.
(8) Sperandeo, N. R.; Brun, R. ChemBioChem 2003, 4, 69.
(9) Nargund, R. P.; Van der Ploeg, L. H. T.; Fong, T. M.; MacNeil, D. J.;
Chen, H. Y.; Marsh, D. J.; Warmke, J. U.S. Pat. Appl. Publ., 2004, 43 pp.
(11) (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203. (b) Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643.
6666 J. Org. Chem. 2008, 73, 6666–6670
10.1021/jo800789p CCC: $40.75 2008 American Chemical Society
Published on Web 07/30/2008

Substituted 1-Acyl-4-iodo-1H-pyrazoles
SCHEME 2
selective route to substituted 1-acyl-4-pyrazoles. Thus, we
synthesized 1-acetyl-5-hydroxy-3,5-diphenyl-4,5-dihydro-1H-
pyrazole (2) as the model system for optimization of this process.
The use of I2 and carbonate bases, such as K2CO3, Li2CO3, and
Na2CO3, in CH2Cl2 or CH3CN provided no reaction of 2. We
then shifted our attention to the use of ICl. ICl has been
established as the most Lewis acidic of the halogens.17 We were
pleased to find that 1.2 equiv of ICl in the presence of 2 equiv
of Na2CO3 in CH2Cl2 provided complete conversion of 2 to
the corresponding 1-acetyl-3,5-diphenyl-1H-pyrazole (19) (60%
yield) and 1-acetyl-4-iodo-3,5-diphenyl-1H-pyrazole (20) (30%
yield) (eq 1).
oximes were prepared by stirring the ynone in the presence of
methoxylamine hydrochloride, pyridine, and Na2SO4 or MgSO4
at room temperature with methanol as the solvent.12
We reasoned that an analogous synthetic strategy could be
applied toward the synthesis of highly substituted pyrazoles.
We envisioned that 2-alkyn-1-one N,N-dimethylhydrazones (1)
would react in the presence of an electrophile to afford
substituted 1-methylpyrazoles (Scheme 2). However, this syn-
thetic strategy was unsuccessful, because we were unable to
prepare the requisite hydrazones, and thus an alternative route
to 4-halopyrazoles was ultimately developed. We wish herein
to report our results on that project.
To increase the solubility of the inorganic base, CH3CN and
MeNO2 were screened as solvents under the same reaction
conditions. However, this provided messy reaction mixtures and
provided none of the desired product. Among carbonate bases
screened, using CH2Cl2 as the solvent in the presence of ICl,
Li2CO3 provided the best results. The use of Li2CO3 nearly
reversed the product ratio, compared with Na2CO3, providing
a 13% yield of 19 and a 52% yield of 20, although the reaction
took two days to reach completion. Omitting Li2CO3 from the
reaction led to the formation of deacylated pyrazole products,
presumably due to the formation of HCl. The optimal reaction
conditions thus far developed involve stirring 0.25 mmol of the
dihydropyrazole 2, 3 equiv of ICl, and 2 equiv of Li2CO3 in
2.5 mL of CH2Cl2 at room temperature, which affords a 95%
yield of 20.
With optimized conditions in hand, we synthesized a number
of 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles from the corre-
sponding 2-alkyn-1-ones (Table 1). In most cases, preparation
of the 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles proceeded
smoothly in good yield by simply heating the appropriate
alkynone in the presence of 2 equiv of acetylhydrazine in toluene
at 80 °C. When R1 is a phenyl group, the reaction proceeds
satisfactorily in most cases. Both the parent system and one
containing an electron-deficient aryl group gave the desired
dihydropyrazoles 2 and 3 in good yields (Table 1, entries 1 and
2). Substituting an n-butyl group on the terminus of the alkyne
moiety was also tolerated well and provided 4 in a good yield
(Table 1, entry 3). Only when R2 ) 1-cyclohexenyl did the
reaction afford only a modest yield of compound 5 (Table 1,
entry 4).
Results and Discussion
The preparation of dimethylhydrazones, such as 1, is not as
straightforward as was first anticipated. Our attempts at the
preparation of dimethylhydrazones, such as 1, by 1,2-addition
of 1,1-dimethylhydrazine to alkynones or by metal-acetylide
additions to hydrazonyl halides did not lead to any desired
products. In addition, copper- and palladium-catalyzed cross-
coupling reactions of terminal acetylenes with hydrazonyl
halides failed to provide the anticipated dimethylhyrazones.
Discouraged by the inability to readily prepare such dimethyl-
hydrazones for subsequent electrophilic cyclization to pyrazoles,
we developed an alternate methodology.
When acyl and aroyl hydrazine derivatives were first allowed
to react with alkynones, the products were originally assigned
an open chain form.13 Since then, their structures have been
reassigned and a small number of 5-hydroxy-4,5-dihydro-1H-
pyrazoles have been reported by the reaction of hydrazine
derivatives with alkynones.13 To the best of our knowledge,
the analogous reaction with acetylhydrazine has not been
reported. 5-Hydroxy-4,5-dihydro-1H-pyrazoles have also been
prepared by the reaction of hydrazine derivatives with 3-alkoxy-
alk-2-en-1-ones.14 The synthesis of 5-hydroxy-4,5-dihydro-1H-
pyrazoles from alkynones is attractive due to the many ways
one can selectively synthesize alkynones from commercially
available starting materials.15
A literature search revealed that iodine has been used as a
Lewis acid for the facile dehydration of aldoximes to nitriles.16
We envisioned that the dehydration of N-acyl-5-hydroxy-4,5-
dihydro-1H-pyrazoles, followed by iodination, could provide a
When the 1 position of the 2-alkyn-1-one was substituted
with a 2-naphthyl group, the reaction gave a yield of 6
comparable to that of the parent system (Table 1, compare
entries 1 and 5). Halogens in the para position of the aromatic
ring, including F, Cl, Br, and trifluoromethyl, provided good
yields of the desired 5-hydroxy-4,5-dihydro-1H-pyrazoles 7, 8,
9, and 10, respectively (Table 1, entries 6-9). The presence of
an electron-withdrawing cyano group in the para position also
gave a good yield of 11 (Table 1, entry 10). Electron-rich aryl
groups, including p-t-Bu, 3,4-OCH2CH2O-, and 3,4,5-tri-
methoxy phenyl groups also worked well and provided good
(12) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem. Soc. 1986, 108,
6016.
(13) (a) Sabri, S. S. J. Heterocycl. Chem. 1986, 23, 727. (b) Holla, B. S.;
Udupa, K. V.; Sridhar, K. R. Bull. Chem. Soc. Jpn. 1989, 62, 3409. (c) Kalluraya,
B.; Shetty, S. N.; Rai, G. Indian J. Chem., Sect. B 2000, 39B, 597.
(14) (a) Bonacorso, H. G.; Oliveira, M. R.; Costa, M. B.; da Silva, L. B.;
Wastowski, A. D.; Zanatta, N.; Martins, M. A. P. J. Heterocycl. Chem. 2005,
42, 631. (b) Bonacoraso, H. G.; Wentz, A. P.; Lourega, R. V.; Cechinel, C. A.;
Moraes, T. S.; Flores, A. F. C.; Zanatta, N.; Martins, M. A. P. J. Heterocycl.
Chem. 2007, 44, 233.
(15) (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977, 777. (b)
Kobayashi, T.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1981, 333. (c)
Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057. (d) Lin, C.-F.; Lu,
W.-D; Wang, I.-W.; Wu, M.-J. Synlett 2003, 2057. (e) Birkofer, L.; Ritter, A.;
Uhlenbraunk, H. Chem. Ber. 1963, 96, 3280.
(16) Saikia, P.; Ilias, M.; Prajapati, D.; Sandhu, J. S. Indian J. Chem., Sect.
B 2002, 41B, 2109.
(17) (a) Drago, R. S.; Wenz, D. A. J. Am. Chem. Soc. 1962, 84, 526. (b)
Scott, R. L. J. Am. Chem. Soc. 1953, 75, 1550.
J. Org. Chem. Vol. 73, No. 17, 2008 6667

Waldo et al.
TABLE 1. Synthesis of
TABLE 2. Synthesis of 1-Acetyl-4-iodopyrazolesa
1-Acetyl-5-hydroxy-4,5-dihydro-1H-pyrazolesa
a Unless otherwise stated, all reactions were carried out in CH2Cl2 (10
mL/mmol) at room temperature with 2.0 equiv of Li2CO3 and 3.0 equiv of
ICl. b Isolated yields after column chromatography. c Yield determined
by NMR spectroscopy. d X-ray crystallographic data are available for
this compound in the Supporting Information. e Four equiv of ICl was
used. f Yield determined by NMR spectroscopy. Nonhalogenated pyra-
zole is the major side product.
a All reactions were carried out using 1.0 mmol of alkynone, 2.0 mmol
of acetylhydrazine in toluene (5 mL) at 80 °C for 6 h unless otherwise
specified. b Isolated yields after column chromatography. c X-ray crystal-
lographic data are available for this compound in the Supporting
Information. d The reaction required 24 h to reach completion.
provided a slightly lower yield of 16 and required a longer
reaction time compared to that of the parent system (Table 1,
compare entries 1 and 15). A 3-pyridyl substituent provided an
excellent yield of 17 (Table 1, entry 16). The reaction also
tolerated a vinylic group in the R1 position, affording cinnamyl
derivative 18 (Table 1, entry 17). Thus, this approach to 1-acyl-
5-hydroxy-4,5-dihydro-1H-pyrazoles appears to be quite general.
With the desired 1-acetyl-5-hydroxy-4,5-dihydropyrazole
derivatives in hand, we studied the scope of the ICl-induced
dehydration/iodination process (Table 2). Under our optimized
yields of 12, 13, and 14, respectively (Table 1, entries 11-13).
The highly electron-rich benzene ring containing a p-Me2N
group provided only a modest yield of 15 and the reaction
required a 4-fold increase in reaction time (Table 1, entry 14).
A methyl group in the ortho position of the benzene ring
6668 J. Org. Chem. Vol. 73, No. 17, 2008

Substituted 1-Acyl-4-iodo-1H-pyrazoles
conditions, pyrazole 20 was obtained in an excellent yield (Table
2, entry 1). Substitution of the phenyl ring in the R2 group by
an electron-withdrawing CO2Et group afforded a slightly lower
yield of 21 as compared to the parent system (Table 2, compare
entries 1 and 2). Replacing the aryl moiety with an alkyl group
also led to the desired pyrazole 22 in an excellent yield (Table
2, entry 3). Unfortunately, introducing a vinylic group in the
R2 position led to only a low yield of the desired pyrazole 23
generally react more readily than their bromine counterparts in
the presence of palladium catalysts due to more facile oxidative
addition.19 1-Acyl-4-halopyrazoles have demonstrated their
importance as intermediates for palladium-catalyzed Sonogashira
cross-coupling reactions leading to compounds of pharmaco-
logical interest.20 Also, the palladium-catalyzed Heck21 cross-
coupling of 1-acyl-4-halopyrazoles has been demonstrated. In
addition, another advantage of this methodology is the fact that
the acylation of pyrazoles often gives a mixture of N-acylated
products,22 leading to unwanted and often inseparable product
mixtures, where our process eliminates this problem. We believe
that this approach to substituted pyrazoles should be quite useful
in synthesis, considering the many ways one can transform the
resulting iodine functional group by catalytic methods other than
those described above.
1
(Table 2, entry 4). Pyrazole 23 was observed by H NMR
spectroscopy. However, inseparable impurities alongside the
product could not be removed by column chromatography.
The lower yield may be attributed to the generation of HCl in
the reaction mixture, which may cause unwanted side reactions
with the 1-cyclohexenyl group or perhaps the ICl is reacting
directly with the carbon-carbon double bond.
We have also studied the effect of varying the nature of the
R1 group, while retaining R2 as a phenyl group. When R1 is a
2-naphthyl group, the reaction proceeded smoothly and gave
an excellent yield of the pyrazole 24, which is comparable to
the yield of the parent system (Table 2, compare entries 1 and
5). Phenyl groups bearing an F, Cl, or Br in the 4-position all
provided the corresponding 4-iodopyrazoles 25, 26, and 27,
respectively, in good yields (Table 2, entries 6-8). The structure
of compound 26 has been confirmed by X-ray analysis. The
presence of a CF3 group in the 4-position of the aromatic ring
also provided the desired 4-iodopyrazole 28 in a good yield
(Table 2, entry 9). Introducing an electron-withdrawing CN
group into the 4-position of the phenyl group of R1 provided
only a modest yield of 4-iodopyrazole 29 and a dramatic
increase in the required reaction time was noted (Table 2, entry
10). Increasing the amount of ICl only provided a modest
increase in yield and the results were within experimental error.
Electron-rich aromatic rings, including 4-t-BuC6H4 and 3,4-
methylenedioxyphenyl, provided good yields of 30 and 31,
respectively (Table 2, entries 11 and 12). To examine the effect
of steric bulk on the benzene ring, we employed compound 16
under our optimized reaction conditions. The reaction proceeded,
although an increased reaction time was required and only a
moderate yield of 32 was obtained. Unfortunately, 32 could not
be separated from its nonhalogenated counterpart (Table 2, entry
13). When R1 was a p-Me2NC6H4 or 3-pyridyl group, the
reaction provided none of the desired 4-iodopyrazoles (Table
2, entries 14 and 15). Despite employing 10 equiv of ICl, 17
failed to react. This observation may be a result of the basic
nitrogen atoms tying up the Lewis acidic ICl, preventing it from
effecting the desired dehydration reaction. Additional equivalents
of ICl were not attempted in the case of compound 15 because
of the likelihood of an unwanted side reaction caused by
iodination of the p-Me2NC6H4 moiety through electrophilic
aromatic substitution. Compound 14 was subjected to our
dehydration conditions to study the effect of an electron-rich
ring in the R1 position and a sterically compact group in the R2
position. This reaction suffered from extended reaction times
and the corresponding pyrazole, minus an iodine moiety, was
Conclusions
A number of new 1-acetyl-5-hydroxy-4,5-dihydro-1H-pyra-
zoles have been synthesized in good to excellent yields from
2-alkyn-1-ones. 3,5-Disubstituted-1-acyl-4-iodo-1H-pyrazoles
have been synthesized in moderate to excellent yields by a novel
dehydration/iodination of 1-acetyl-5-hydroxy-4,5-dihydro-1H-
pyrazoles under mild reaction conditions. Our methodology is
fairly general and provides a selective route to 1-acyl-4-
iodopyrazoles. To the best of our knowledge, this is the first
report of an ICl-induced dehydration of a heterocyclic derivative
that provides iodinated pyrazoles.
Experimental Section
General Procedure for Preparation of the 1-Acetyl-5-hy-
droxy-4,5-dihydro-1H-pyrazoles. The alkynone (1.0 mmol) and
acetylhydrazine (2.0 mmol, 148.2 mg) in toluene (5 mL) were
heated to 80 °C with stirring. The reaction was monitored by TLC
until the reaction was complete. The solution was concentrated
under vacuum to yield the crude product, which was purified by
flash chromatography on silica gel with CH2Cl2/EtOAc as the eluent.
1-Acetyl-5-hydroxy-3,5-diphenyl-4,5-dihydro-1H-pyrazole (2).
Purification by flash chromatography (15:1 CH2Cl2/EtOAc) afforded
194 mg (77%) of the product as a colorless solid: mp 139-141
°C; 1H NMR (CDCl3 300 MHz) δ 2.44 (s, 1H), 3.33-3.39 (d, J )
18.3 Hz, 1H), 3.67-3.73 (d, J ) 18.2 Hz, 1H), 5.12 (s, 1H),
7.29-7.43 (m, 8H), 7.69-7.72 (m, 2H); 13C NMR (CDCl3) δ 22.5,
50.7, 94.0, 124.1, 126.8, 128.4, 129.0, 130.7, 131.4, 144.0, 152.8,
171.1 (1 peak missing due to overlap); HRMS calcd for C17H16N2O2
280.1212, found 280.1221.
General Procedure for Dehydration/Iodination of 1-Acetyl-
5-hydroxy-4,5-dihydro-1H-pyrazoles with ICl. The appropriate
1-acetyl-5-hydroxy-4,5-dihydro-1H-pyrazole (0.25 mmol) and finely
powdered Li2CO3 (0.5 mmol) in CH2Cl2 (2.5 mL) were allowed to
stir vigorously for 5 min at room temperature. To the vigorously
stirred slurry, in the absence of light, was slowly added a freshly
prepared solution of ICl (1 M in CH2Cl2, 3.0 equiv) and the solution
was allowed to stir at room temperature. The reaction was monitored
by TLC to establish completion. The excess ICl was removed by
washing with a saturated aqueous solution of Na2S2O3. The aqueous
solution was then extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were dried over anhydrous MgSO4 and concentrated
1
detected as the major side product by H NMR spectroscopy,
along with 4-iodopyrazole 33 (Table 2, entry 16).
The advantage of this methodology is that 1-acyl-4-iodo-3,5-
disubstituted-1H-pyrazoles can be synthesized selectively from
the corresponding alkynones under mild reaction conditions. To
the best of our knowledge, the iodination of 1-acylpyrazoles
has not been reported, although bromination has.18 Aryl iodides
(19) Jutand, A.; Mosleh, A. Organometallics 1995, 14, 1810.
(20) (a) Rodriguez-Franco, M. I.; Dorronsoro, I.; Martinez, A. Synthesis 2001,
1711. (b) Carson, J. R. Chem. Abstr. 1987, 107, 477423. McNeilab, Inc., USA,
U.S. Patent 4,663,334.
(21) Kwok, T. J.; Virgilio, J. A. Org. Process Res. DeV. 2005, 9, 694.
(22) (a) Baddar, F. G.; Al-Hajjar, F. H.; El-Rayyes, N. R. J. Heterocycl.
Chem. 1978, 15, 385. (b) Baddar, F. G.; Al-Hajjar, F. H.; El-Rayyes, N. R.
J. Chem. Eng. Data 1982, 27, 213.
(18) Soliman, R.; Darwish, S. A. S. J. Med. Chem. 1983, 26, 1659.
J. Org. Chem. Vol. 73, No. 17, 2008 6669

Waldo et al.
under vacuum to yield the crude product, which was purified by
flash chromatography on silica gel with hexanes/EtOAc as the
eluent.
Excellence for Chemical Methodologies and Library Develop-
ment (P50 GM069663) for support of this research, and Johnson
Matthey, Inc. and Kawaken Fine Chemicals Co., Ltd. for
donations of palladium catalysts. We also thank Dr. Arkady
Ellern for the X-ray analysis of compounds 8 and 26.
1-Acetyl-4-iodo-3,5-diphenyl-1H-pyrazole (20). Purification by
flash chromatography (9:1 hexanes/EtOAc) afforded 92.2 mg (95%)
of the product as an off-white solid: mp 86-88 °C; 1H NMR
(CDCl3 300 MHz) δ 2.75 (s, 3H), 7.34-7.38 (dd, J ) 3.8, 7.4 Hz,
2H), 7.44-7.53 (m, 6H), 7.90-7.93 (m, 2H); 13C NMR (CDCl3)
δ 23.1, 71.7, 128.4, 128.6, 128.9, 129.4, 129.5, 129.8, 131.4, 131.9,
148.1, 154.3, 169.4; HRMS calcd for C17H13IN2O 388.0073, found
388.0085.
Supporting Information Available: Characterization of
previously unknown starting materials and final products,
including full 1H and 13C NMR spectra, and the X-ray structures
of compounds 8 and 26, including CIF files and crystallographic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We thank the National Institute of General
Medical Sciences (R01 GM070620 and R01 GM079593) and
the National Institutes of Health Kansas University Center of
JO800789P
6670 J. Org. Chem. Vol. 73, No. 17, 2008