Facile route to tetrasubstituted pyrazoles utilizing ceric ammonium nitrate

Article abstract of DOI:10.1055/s-0029-1217163

A convenient approach for the synthesis of tetrasubstituted pyrazoles is described. The method involves the treatment of 1,3-diketones and allyltrimethylsilane with CAN followed by ceriumcatalyzed addition of substituted hydrazines to construct pyrazoles in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217163

NIH Public Access
Author Manuscript
Synlett. Author manuscript; available in PMC 2010 December 8.
Published in final edited form as:
Synlett. 2009 ; (9): 1490–1494. doi:10.1055/s-0029-1217163.
Facile Route to Tetrasubstituted Pyrazoles Utilizing Ceric
Ammonium Nitrate
*
James J. Devery III, Pramod K. Mohanta, Brian M. Casey, and Robert A. Flowers II
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA
Abstract
A convenient approach for the synthesis of tetrasubstituted pyrazoles is described. The method
involves the treatment of 1,3-diketones and allyltrimethylsilane with CAN followed by cerium-
catalyzed addition of substituted hydrazines to construct pyrazoles in good yields.
Keywords
heterocycles; pyrazoles; ceric ammonium nitrate; allylation; hydrazines
Pyrazoles have numerous applications in both the pharmaceutical and agrochemical
1
industries. Recent work has shown the utility of pyrazole motifs as HIV-1 reverse
2
3
4
5
transcriptase inhibitors, antidiabetics, COX-2 inhibitors,
A
receptor antagonists, CB1
2A
6
7
receptor antagonists, transforming growth factor-β receptor type I inhibitors, DNA
8
9
intercalating agents, and estrogen receptor ligands. Due to the importance of pyrazoles,
alternative synthetic routes to their production are useful.
Ceric ammonium nitrate (CAN) has long been used in organic synthesis as both an oxidant
and a Lewis acid for functional-group conversion and promotion of bond-forming reactions.
10 Our group has been exploring the mechanism and use of this reagent.11 In particular, we
have explored several reactions involving the oxidative coupling of β-diketones and
radicophiles using Ce(IV) reagents. 12 Recently, CAN has been shown to be an efficient
Lewis acid catalyst in the synthesis of β-enaminoketones. 13 Based on this precedent and
our previous experience with CAN, we reasoned that highly substituted pyrazoles could be
synthesized through the Ce(IV)-initiated reaction of a radicophile and a β-diketone, followed
by reaction with an appropriately substituted hydrazine. To test this supposition, an initial
experiment was performed using 2,4-pentanedione as the diketone. The diketone was treated
with 2.1 equivalents CAN in the presence of 1.3 equivalents allyltrimethylsilane in
acetonitrile (MeCN). After loss of the yellow color of Ce(IV), 1.4 equivalents of
phenylhydrazine hydrochloride was added to the solution. The reaction was stirred for 3
hours yielding 3a with a one-pot yield of 68%. This procedure was then applied to a variety
of hydrazines providing tetrasubstituted pyrazoles in moderate to good isolated yields as
shown in Table 1.
Next, the one-pot method was applied to diaryl β-diketones. Unfortunately, significantly
lower yields of pyrazole were obtained. To achieve better conversions, the reaction was run
in two steps. First, allylation of the diketone was performed under the one-pot conditions.
The allylated diketone was isolated and then added to a solution of 1.4 equivalents hydrazine
© Georg Thieme Verlag Stuttgart · New York
Fax +1(610)7586536; rof2@lehigh.edu.

Devery et al.
Page 2
and 3 mol% CAN in MeCN. The solution was refluxed for 3 hours yielding tetrasubstituted
pyrazoles in modest overall yields (Table 2).
In addition to examining various diketones, the impact of modifying the radicophile was
examined. Dibenzoylmethane was treated with CAN in the presence of methyl
allyltrimethylsilane. Rotary evaporation under reduced pressure and washing with water and
CH Cl resulted in the isolation of dihydrofuran 7 instead of the anticipated 6e. It is likely
2
2
that during the workup, olefin 6e is activated either by Lewis acid interaction with Ce(III) or
through protonation by a free ammonium. Addition to the activated olefin by the pendant
carbonyl followed by elimination leads to 7. To circumvent this process and reduce furan
production, triethylamine was added dropwise after completion of the reaction to neutralize
the acidic medium. Using this alternative workup procedure, production of 7 is minimized,
allowing 6e to be isolated in a 52% yield (Scheme 1). Subsequent reaction of 6e with either
methylhydrazine or p-methoxyphenylhydrazine produced pyrazoles 8e and 8f in moderate
overall yields (Table 2, entries 5 and 6).
Many synthetically relevant pyrazoles possess different substituents at the C3 and C5
positions. In order to effectively synthesize these species from unsymmetric diketones,
regioselectivity is required for production of single isomers. To examine the regioselectivity
of our approach, benzoylacetone was employed as a model substrate (Table 3). Oxidative
allylation, isolation, and subsequent reaction of p-methoxyphenylhydrazine hydrochloride in
the presence of a catalytic amount of CAN (3 mol%) led to a 16:1 ratio of regioisomers as
1
determined by H NMR. Separation of the isomers via flash chromatography and analysis
1
by H NMR showed that the major and minor products were 10a and 10b, respectively.
To examine the basis of the regioselectivity, a series of 1-phenyl-β-diketones with varied
substitution on the hydrazine and the 2-position of the diketone was explored. When
methylhydrazine was used, 11a was formed almost exclusively. Replacement of the 2-allyl
group with a methyl substituent was examined next. Reaction of 2-methyl-1-phenyl-1,3-
butanedione with p-methoxyphenylhydrazine hydrochloride and 3 mol% CAN provided
pyrazoles 12a and 12b in a 6:1 ratio. An attempt to alter the electronic nature of the diketone
through the use of 2-allyl-4,4,4-trifluoro-1-phenyl-1,3-butanedione resulted in a single
isomer (Table 3, entry 4). Unfortunately, after extensive analysis using 1D and 2D NMR,
14
the structure of the isomer could not be identified.
Taken together, these limited observations are consistent with product formation resulting
from steric interactions encountered upon initial nucleophilic attack of the hydrazine on the
diketone. Comparison of entries 1 and 2 in Table 3 shows that altering the size of the
substituent on the hydrazine impacts the selectivity. During the course of the reaction, initial
reversible formation of the hydrazone is followed by ring closure. Nucleophilic attack of the
hydrazine on the carbonyl adjacent to the methyl group of benzoylacetone leads to a
3
hydrazone at the 3-position. Subsequent ring closure places R in close proximity to the 1-
3
phenyl group of the intermediate. A smaller R substituent is likely to lead to ring closure
more efficiently than a larger substituent as observed for the relative regioselectivities for 10
and 11. In the case of the example in entry 3 of Table 3, decreasing the size of the
substituent in the 2-position of the diketone from an allyl to a methyl reduces steric
crowding around both carbonyls, decreasing the overall selectivity for 12.
To examine the practical use of this method, the synthesis of propylpyrazole triol (PPT) 14,
9
an estrogen receptor agonist, was attempted. Dropwise addition of CAN dissolved in
MeCN to 1,3-bis(4-methoxyphenyl)-1,3-propanedione (4d) and allyltrimethylsilane in
MeCN produced diketone 6d in 66% isolated yield. Refluxing a slight excess of p-
methoxyphenylhydrazine hydrochloride with 6d in the presence of 3 mol% CAN provided
Synlett. Author manuscript; available in PMC 2010 December 8.

Devery et al.
Page 3
8d in a 68% yield. Reduction of 8d by Pd/C hydrogenation followed by deprotection with
Br B provided 14 in an overall yield of 30% in four steps.
3
In conclusion, a variety tetrasubstituted pyrazoles can be synthesized from Ce(IV)-initiated
reaction of allyltrimethylsilane and a β-diketone, followed by reaction with an appropriately
substituted hydrazine. Both aliphatic and aromatic diketones can be employed with a range
of substituted hydrazines leading to highly substituted and complex products from readily
16–
available starting materials.
18
Acknowledgments
RAF is grateful to the National Institutes of Health (1R15GM075960-01) for support of this work.
References and Notes
1. Shinkai, I. Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982–1995: The
Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds. Shinkai, I., editor. Vol. Vol.
3. Oxford UK: Pergamon; 1996. p. 1-75.
2. Genin MJ, Biles C, Keiser BJ, Poppe SM, Swaney SM, Tarpley WG, Yagi Y, Romero DL. J. Med.
Chem 2000;43:1034. [PubMed: 10715167]
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P, Strohschein RJ, Schuster HF, Wilson M, Xu DD. J. Med. Chem 2001;44:2601. [PubMed:
11472214]
4. (a) Regan J, Breitfelder S, Cirillo P, Gilmore T, Graham AG, Hickey E, Klaus B, Madwed J, Moriak
M, Moss N, Pargellis C, Pav S, Proto A, Swinamer A, Tong L, Torcellini C. J. Med. Chem
2002;45:2994. [PubMed: 12086485] (b) Palomer A, Cabre F, Pascual J, Campos J, Trujillo MA,
Entrena A, Gallo MA, Garcia L, Mauleon D, Espinosa A. J. Med. Chem 2002;45:1402. [PubMed:
11906281] (c) Elzein E, Kalla RV, Li X, Perry T, Gimbel A, Zeng D, Lustig D, Leung K, Zablocki
J. J. Med. Chem 2008;51:2267. [PubMed: 18321039]
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Malany S, Joswig T, Santos M, Gross RS, Williams JP, Castro-Palomino JC, Crespo MI, Prat M,
Gual S, Díaz J-L, Jalali K, Sai Y, Zuo Z, Yang C, Wen J, O’Brien Z, Petroski R, Saunders J. J.
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HR, Dierks EA, Anderson BD, Britt KS, Huss KL, Voss MD, Wang Y, Clawson DK, Yingling JM,
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2009 in press.
9. (a) Fink BE, Mortensen DS, Stauffer SR, Aron ZD, Katzenellenbogen JA. Chem. Biol 1999;6:205.
[PubMed: 10099132] (b) Kraichely D, Sun J, Katzenellenbogen J, Katzenellenbogen B.
Endocrinology 2000;141:3534. [PubMed: 11014206] (c) Stauffer SR, Coletta CJ, Tedesco R,
Nishiguchi G, Carlson K, Sun J, Katzenellenbogen BS, Katzenellenbogen JA. J. Med. Chem
2000;43:4934. [PubMed: 11150164]
10. (a) Molander GA. Chem. Rev 1992;92:29. (b) Nair V, Mathew J, Prabhakaran J. Chem. Soc. Rev
1997;26:127.
11. (a) Zhang Y, Jiao J, Flowers RA. J. Org. Chem 2006;71:4516. [PubMed: 16749782] (b) Jiao J,
Zhang Y, Devery JJ, Xu L, Deng J, Flowers RA. J. Org. Chem 2007;72:5486. [PubMed:
17602587]
12. (a) Zhang Y, Raines AJ, Flowers RA. Org. Lett 2003;5:2363. [PubMed: 12816449] (b) Zhang Y,
Flowers RA. J. Org. Chem 2003;68:4560. [PubMed: 12762771]
13. Sridharan V, Avendaño,Avendaño C, Menéndez JC. Synlett 2007:881.
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Page 4
15. All reactions were run at room temperature unless specified otherwise.
16. One-Pot Procedure for 4-Allyl-1,3,5-trisubstituted PyrazolesTo a mixture of 1,3-dione (1
equiv) and allyltrimethylsilane (1.3 equiv) in MeCN, CAN (2.1 equiv) dissolved in MeCN was
added dropwise. The solution was stirred at r.t. until the color disappeared completely (20–45
min). Hydrazine (1.4 equiv) was added and stirred at r.t. for 3.5–6 h (monitored by GC). Solvent
was removed by rotary evaporation. Ice-cold water was added to the solid residue and extracted
with CH Cl . The combined organic extract was dried over MgSO and concentrated by rotary
2
2
4
evaporation. The residue was purified with SiO column chromatography eluting with hexanes–
2
1
EtOAc.4-Allyl-1-(4-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole (3c)Yield 74% (0.89 g). H
NMR (500 MHz, CDCl ): δ = 2.13 (s, 3 H, Me), 2.21 (s, 3 H, Me), 3.14 (d, J = 5.0 Hz, 2 H, CH ),
3
2
3.82 (s, 3 H, OMe), 4.98 (d, J = 8.5 Hz, 1 H, CH), 4.99 (br s, 1 H, CH), 5.85 (m, 1 H), 6.93 (d, J =
13
8.2 Hz, 2 H, ArH), 7.28 (d, J = 8.5 Hz, 2 H, ArH). C NMR (125 MHz, CDCl ): δ = 10.65,
3
11.87, 27.99, 55.51, 114.09, 114.51, 114.54, 126.36, 133.31, 136.50, 136.61, 147.6, 158.67.
+
HRMS–FAB: m/z = calcd for C
H N O [MH] : 243.1497; found: 243.1488.4-Allyl-1-(2,4-
15 19 2
1
dinitro-phenyl)-3,5-dimethyl-1H-pyrazole (3d)Yield 63% (0.48 g). H NMR (500 MHz,
CDCl ): δ = 2.15 (s, 3 H, Me), 2.16 (s, 3 H, Me), 3.15 (d, J = 5.7 Hz, 2 H, CH ), 4.75 (d, J = 17.2
3
2
Hz, 1 H, CH), 5.03 (d, J = 10.0 Hz, 1 H, CH), 5.85 (m, 1 H), 7.67 (d, J = 8.7 Hz, 1 H, ArH), 8.49
13
(d, J = 7.9 Hz, 1 H, ArH), 8.76 (s, 1 H, ArH). C NMR (125 MHz, CDCl ): δ = 10.2, 11.9, 27.56,
3
115.25, 117.39, 121.0, 127.26, 129.18, 135.25, 137.82, 138.11, 145.44, 145.95, 151.92. HRMS–
+
FAB: m/z calcd for [MH] C
H N O : 303.1093; found: 303.1071.4-Allyl-1-(4-
14 15 4 4
1
toluenesulfonyl)-3,5-dimethyl-1H-pyrazole (3e)Yield 67% (0.68 g). H NMR (500 MHz,
CDCl ): δ = 2.10 (s, 3 H, Me), 2.36 (br s, 6 H, 2 × Me), 2.98 (d, J = 5.7 Hz, 2 H, CH ), 4.75 (dd, J
3
2
= 1.7, 17.1 Hz, 1 H, CH), 4.92 (dd, J = 1.5, 10.1 Hz, 1 H, CH), 5.69 (m, 1 H), 7.25 (d, J = 8.4 Hz,
13
2 H, ArH), 7.77 (d, J = 8.8 Hz, 2 H, ArH). C NMR (125 MHz, CDCl ): δ = 11.23, 12.29, 22.6,
3
27.18, 115.30, 118.79, 127.41, 129.77, 134.74, 135.44, 140.33, 144.91, 153.49. HRMS–FAB: m/z
+
calcd for [MH] C
H N O S: 291.1167; found: 291.1178.4-(4-Allyl-3,5-dimethyl-pyrazol-1-
15 19 2 2
1
yl)-benzoic Acid (3f)Yield 65% (0.58 g). H NMR (500 MHz, CDCl ): δ = 2.26 (s, 3 H, Me),
3
2.27 (s, 3 H, Me), 3.15 (d, J = 5.8 Hz, 2 H, CH ), 4.98 (d, J = 17.1 Hz, 1 H, CH), 5.0 (d, J = 10.1
2
Hz, 1 H, CH), 5.85 (m, 1 H), 7.54 (d, J = 8.4 Hz, 2 H, ArH), 8.15 (d, J = 8.5 Hz, 2 H, ArH), 9.98
13
(br s, 1 H, OH). C MR (125 MHz, CDCl ): δ = 11.21, 11.73, 27.76, 114.93, 116.53, 123.71,
3
+
127.77, 131.13, 135.85, 136.89, 143.92, 149.37, 170.42. HRMS–FAB: m/z calcd for [MH] :
C
H N O : 257.1290; found: 257.1287.4-Allyl-3,5-diethyl-1-methyl-1H-pyrazole (3g)Yield
15 17 2 2
1
76% (0.68 g). H NMR (500 MHz, CDCl ): δ = 1.09 (t, J = 7.5 Hz, 3 H, Me), 1.18 (t, J = 7.5 Hz,
3
3 H, Me), 2.49–2.52 (two quart are overlapping, 2 × 2 H, 2 × CH ), 3.08 (dd, J = 1.6, 4.7 Hz, 2 H,
2
CH ), 3.71 (s, 3 H, Me), 4.91 (d, J = 7.3 Hz, 1 H, CH), 4.93 (d, J = 7.8 Hz, 1 H, CH), 5.86 (m, 1
2
13
H). C NMR (125 MH , CDCl ): δ = 13.55, 13.89, 17.4, 19.81, 27.67, 35.73, 113.1, 114.26,
Z
3
+
137.53, 141.92, 151.26. HRMS–FAB: m/z calcd for C
H N [MH] : 179.1548; found:
11 19 2
179.1572.
17. Typical Procedure for Pyrazole SynthesisAn MeCN soln of 2-substituted diketone (1 equiv),
hydrazine (1.4 equiv), and CAN (3 mol%) was refluxed for 3 h. Reaction mixture was cooled
down to r.t. Solvent was removed by rotary evaporation. The residue was dissolved with CH Cl ,
2
2
and washed with H O. The organic layer was separated, dried over anhyd MgSO , and
2
4
concentrated by rotary evaporation. The crude reaction mixture was purified by SiO column
2
chromatography eluted with hexanes–EtOAc.4-Allyl-1,3,5-triphenyl-1H-pyrazole (8b)Yield 72%
1
(0.24 g). H NMR (500 MHz, CDCl ): δ = 3.34 (dd, J = 1.9, 3.3 Hz, 2 H, CH ), 5.02 (dd, J = 1.8,
3
2
17.0 Hz, 1 H, CH), 5.11 (dd, J = 1.8, 10.3 Hz, 1 H, CH), 6.00 (m, 1 H), 7.24–7.25 (m, 1 H, ArH),
7.27–7.30 (m, 4 H, ArH), 7.31–7.33 (m, 6 H, ArH), 7.34 (t, 2 H, J = 6.5 Hz, ArH), 7.42 (d, 2 H, J
13
= 6.7 Hz, ArH). C NMR (125 MHz, CDCl ): δ = 28.16, 115.85, 115.93, 124.7, 126.76, 127.7,
3
127.93, 128.32, 128.37, 128.42, 128.66, 129.91, 130.61, 133.65, 137.61, 140.13, 142.0, 151.48.
+
HRMS–FAB: m/z calcd for C
H N [MH] : 337.1705; found: 303.1721.4-Allyl-1-(4-
24 21 2
1
methoxyphenyl)-3,5-diphenyl-1H-pyrazole (8c)Yield 76% (0.63 g). H NMR (500 MHz,
CDCl ): δ = 3.34 (br s, 2 H, CH ), 3.76 (s, 3 H, OMe), 5.00 (d, 1 H, J = 18.4 Hz, CH), 5.08 (d, 1
3
2
H, J = 9.3 Hz, CH), 5.98 (m, 1 H), 6.79 (br d, 2 H, J = 6.1 Hz, ArH), 7.22–7.25 (m, 4 H, ArH),
13
7.29–7.32 (m, 4 H, ArH), 7.42 (br d, 2 H, ArH), 7.81 (d, 2 H, J = 6.7 Hz, ArH). C NMR (125
MHz, CDCl ): δ = 28.22, 55.39, 113.86, 115.44, 115.75, 126.15, 127.59, 127.93, 128.20, 128.34,
3
128.36, 128.57, 128.86, 129.96, 130.67, 133.52, 133.79, 137.67, 141.98, 151.06, 158.36. HRMS–
+
FAB: m/z calcd for C
H N O [MH] : 367.1810; found: 367.1826.
25 23 2
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Devery et al.
Page 5
18. Alternative Workup Procedure for Methylallylation (8e and 8f only)Upon completion of
allylation, an excess of Et N was added dropwise to the reaction mixture. Solvent was removed by
3
rotary evaporation. The residue was dissolved with CH Cl , and washed with H O. The organic
2
2
2
layer was separated, dried over anhyd MgSO , and concentrated by rotary evaporation. The crude
4
reaction mixture was purified by SiO column chromatography eluted with hexanes–EtOAc.1-
2
1
Methyl-4-(2-methylallyl)-3,5-diphenyl-1H-pyrazole (8e)Yield 84% (0.24 g), H NMR (500
MHz, CDCl ): δ = 1.69 (s, 3 H, Me), 3.11 (s, 2 H, CH ), 3.81 (s, 3 H, Me), 4.61 (s, 1 H, CH), 4.64
3
2
(s, 1 H, CH), 7.30 (d, J = 6.9 Hz, 1 H, ArH), 7.38–7.45 (m, 7 H, ArH), 7.71 (br d, J = 7.2 Hz, 2 H,
13
ArH). C NMR (125 MHz, CDCl ): δ = 23.06, 32.19, 37.26, 111.47, 114.1, 127.23, 127.44,
3
127.94, 128.26, 128.47, 128.5, 129.48, 130.35, 133.97, 143.01, 145.3, 149.71. HRMS–FAB: m/z
+
calcd for C
H
20 21
N [MH] : 289.1705; found: 289.1722.1-(4-Methoxyphenyl)-4-(2-
2
1
methylallyl)-3,5-diphenyl-1H-pyrazole (8f)Yield 70% (0.79 g). H NMR (500 MHz, CDCl ): δ
3
= 1.78 (s, 3 H, Me), 3.20 (s, 2 H, CH ), 3.79 (s, 3 H, OMe), 4.75 (s, 1 H, CH), 4.95 (s, 1 H, CH),
2
6.81 (d, J = 7.2 Hz, 2 H, ArH), 7.25 (m, 4 H, ArH), 7.32 (br t, J = 7.1 Hz, 4 H, ArH), 7.42 (d, J =
13
7.4 Hz, 2 H, ArH), 7.81 (d, J = 7.1 Hz, 2 H, ArH). C NMR (125 MHz, CDCl ): δ = 23.28,
3
32.33, 55.39, 111.87, 113.84, 115.78, 126.14, 127.52, 127.70, 128.14, 128.57, 129.68, 129.88,
+
133.51, 133.74, 142.03, 145.47, 151.19, 158.3. HRMS–FAB: m/z calcd for C
H N O [M] :
26 24 2
380.1889; found: 380.1891.4-Allyl-1-(4-methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazole
1
(10a)Yield 45% (0.30 g). H NMR (500 MHz, CDCl ): δ = 2.29 (s, 3 H, Me), 3.15 (dt, J = 5.6, 1.7
3
Hz, 2 H, CH ), 3.75 (s, 3 H, Me), 4.98 (ddt, J = 20.0, 1.8, 1.8 Hz, 1 H, CH), 5.03 (ddt, J = 10.3,
2
1.7, 1.7 Hz, 1 H, CH), 5.90 (ddt, J = 17.0, 10.0, 5.6 Hz, 1 H, CH), 6.75 (m, J = 9.1 Hz, 2 H, ArH),
13
7.09 (m, J = 9.1 Hz, 2 H, ArH), 7.13–7.15 (m, 2 H, ArH), 7.27–7.30 (m, 3 H, ArH). C NMR
(125 MHz, CDCl ): δ = 12.01, 27.85, 55.37, 113.82, 114.94, 115.94, 126.03, 127.97, 128.33,
3
129.75, 130.72, 133.50, 136.83, 140.81, 148.45, 158.12. HRMS–FAB: m/z calcd for C
H N O
20 20 2
+
[M] : 304.1576; found: 304.1570.4-Allyl-1-(4-methoxyphenyl)-5-methyl-3-phenyl-1H-pyrazole
1
(10b)Yield 27% (0.16 g). H NMR (500 MHz, CDCl ): δ = 2.21 (s, 3 H, Me), 3.34 (dt, J = 5.5,
3
1.8 Hz, 2 H, CH ), 3.84 (s, 3 H, Me), 5.02 (ddt, J = 17.0, 1.8, 1.8 Hz, 1 H, CH), 5.08 (ddt, J =
2
10.3, 1.8, 1.6 Hz, 1 H, CH), 5.99 (ddt, J = 17.3, 10.5, 5.5 Hz, 1 H, CH), 6.97 (m, J = 8.9 Hz, 2 H,
ArH), 7.30–7.34 (m, J = 7.5 Hz, 1 H, ArH), 7.37–7.41 (m, 4 H, ArH), 7.66–7.68 (m, 2 H,
13
ArH). C NMR (125 MHz, CDCl ): δ = 10.85, 28.28, 55.61, 113.83, 114.19, 115.20, 126.63,
3
127.97, 128.33, 133.17, 133.88, 136.72, 138.05, 150.76, 159.00, 195.65. HRMS–FAB: m/z calcd
+
for C
H
20 20
N O [M] : 304.1576; found: 304.1577.4-Allyl-1,3-dimethyl-5-phenyl-1H-pyrazole
2
1
(11a)Yield 78% (0.63 g). H NMR (500 MHz, CDCl ): δ = 2.21(s, 3 H, Me), 3.05 (m, 2 H, CH ),
3
2
3.69 (s, 3 H, NMe), 4.88 (dd, J = 1.8, 7.0 Hz, 1 H, CH), 4.95 (dd, J = 1.7, 11.0 Hz, 1 H, CH), 5.82
13
(m, 1 H), 7.26–7.28 (m, 2 H, ArH), 7.37–7.45 (m, 3 H, ArH). C NMR (125 MHz, CDCl ): δ =
3
11.85, 27.81, 36.77, 114.41, 114.61, 128.4, 128.55, 129.6, 130.52, 136.99, 141.85, 146.68.
+
HRMS–FAB: m/z calcd for C
H N [M] : 213.1392; found: 213.1387.1-(4-
14 17 2
1
Methoxyphenyl)-3,4-dimethyl-5-phenyl-1H-pyrazole (12a)Yield 68% (0.37 g). H NMR (500
MHz, CDCl ): δ = 2.01 (s, 3 H, CH ), 2.31 (s, 3 H, Me), 3.71 (s, 3 H, OMe), 6.74 (d, J = 7.2 Hz, 2
3
3
13
H, ArH), 7.12 (m, 4 H, ArH), 7.27 (m, 3 H, ArH). C NMR (125 MHz, CDCl ): δ = 8.52, 11.84,
3
55.21, 113.69, 113.93, 125.91, 127.65, 128.21, 129.63, 130.83, 133.40, 140.13, 148.06, 157.94.
+
HRMS–FAB: m/z calcd for C
H N O [M] : 278.1419; found: 278.1412.1-(4-
18 18 2
1
Methoxyphenyl)-4,5-dimethyl-3-phenyl-1H-pyrazole (12b)Yield 11% (0.06 g). H NMR (500
MHz, CDCl ): δ = 2.19 (s, 3 H, Me), 2.23 (s, 3 H, Me), 3.84 (s, 3 H, OMe), 6.96 (d, J = 9.0 Hz, 2
3
13
H, ArH), 7.27–7.31 (m, 2 H, ArH), 7.37–7.41 (m, 3 H, ArH), 7.71 (d, J = 8.0 Hz, 2 H, ArH).
C
NMR (125 MHz, CDCl ): δ = 9.76, 10.85, 55.58, 114.19, 125.41, 126.59, 127.28, 127.81, 127.90,
3
+
128,34, 134.25, 137.34, 150.30, 158.92. HRMS–FAB: m/z calcd for C
H N O [M] : 278.1419;
18 18 2
found: 278.1422.4-Allyl-1-(4-methoxyphenyl)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole
1
(13)Yield 68% (0.49 g). H NMR (500 MHz, CDCl ): δ = 3.27 (d, J = 3.6 Hz, 2 H, CH ), 3.75 (s,
3
2
3 H, Me), 4.94 (d, J = 17.2 Hz, 1 H, C=CH), 5.03 (d, J = 10.5 Hz, 1 H, C=CH), 5.89 (m, 1 H,
13
C=CH), 6.77 (d, J = 8.8 Hz, 2 H, ArH), 7.14 (m, 4 H, ArH), 7.33 (m, 3 H, ArH). C NMR (125
MHz, CDCl ): δ = 27.38, 55.16, 113.98, 115.58, 116.63, 122.25 (q, J = 271 Hz, CF ), 126.40,
3
3
128.65, 128.96, 129.07, 129.99, 132.45, 136.43, 141.05 (q, J = 37 Hz), 142.83, 159.17. HRMS–
+
FAB: m/z calcd for C
H F N O [M] : 358.1293; found: 358.1301.
20 17 3 2
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Devery et al.
Page 6
Scheme 1.
Dihydrofuran formation
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Devery et al.
Page 7
Scheme 2.
15
Reagents and conditions: (i) allyltrimethylsilane (1 equiv), CAN (2.1 equiv), MeCN, 45
min; (ii) p-methoxyphenylhydrazine hydrochloride (1.4 equiv), CAN (3 mol%), MeCN,
reflux, 3 h; (iii) Pd/C (5 wt%), MeOH, H (100 psi), 14 h; (iv) Br B (6 equiv), CH Cl , −78
2
3
2
2
°C, 1.5 h.
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Devery et al.
Page 8
Table 1
Pyrazoles from Aliphatic Diketones
R1
R2
Entry
Product
a
Yield (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Et
Ph
68
85
71
63
67
65
76
Me
4-MeOC6H4
2,4-DNP
Ts
4-COOHC6H4
Me
3g
a
Isolated yield.
Synlett. Author manuscript; available in PMC 2010 December 8.

Devery et al.
Page 9
Synlett. Author manuscript; available in PMC 2010 December 8.

Devery et al.
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Synlett. Author manuscript; available in PMC 2010 December 8.