Vinylogous reactivity of enol diazoacetates with donor-acceptor substituted hydrazones. Synthesis of substituted pyrazole derivatives

Article abstract of DOI:10.1021/jo302696y

A regiospecific synthesis of multifunctional pyrazoleshas been developed from a cascade process triggered by Rh(II)-catalyzed dinitrogen extrusion from enol diazoacetates with vinylogous nucleophilic addition followed by Lewis acid catalyzed cyclization a

Full text of DOI:10.1021/jo302696y

Article
pubs.acs.org/joc
Vinylogous Reactivity of Enol Diazoacetates with
Donor−Acceptor Substituted Hydrazones.
Synthesis of Substituted Pyrazole Derivatives
Xinfang Xu,† Peter Y. Zavalij,† Wenhao Hu,‡ and Michael P. Doyle*,†
†Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
‡Shanghai Engineering Research Center for Molecular Therapeutics and New Drug Discovery and Development,
East China Normal University, 3663 Zhongshan Bei Road, Shanghai 200062, People’s Republic of China
S
* Supporting Information
ABSTRACT: A regiospecific synthesis of multifunctional pyrazoles
has been developed from a cascade process triggered by Rh(II)-
catalyzed dinitrogen extrusion from enol diazoacetates with
vinylogous nucleophilic addition followed by Lewis acid catalyzed
cyclization and aromatization.
which Rh2((R)-PTL)4 catalyzed highly enantioselective vinylogous
N−H insertion; a subsequent Sc(OTf)3-catalyzed Mannich
addition generated the corresponding tetrahydropyridazine
derivatives 3 in high yield and diastereoselectivity (eq 1).7
INTRODUCTION
■
Diazo compounds have been extensively studied during the last
few decades, and their value in organic synthesis is well-known.1,2
Direct dipolar cycloaddition to α,β-unsaturated carbonyl com-
pounds and nitriles3 as well as catalytic processes have provided
effective methodologies for the synthesis of heterocyclic com-
pounds.4 Catalytic generation of metal carbenes for heterocyclic
syntheses has been performed with diazocarbonyl compounds
ranging from diazoacetates4e,g and diazomalonates3e to diazo
ketones4a,f and diazoacetoacetates,4d although vinyldiazoace-
tates have also been employed.1a A key element in the uses of
these diazo compounds is the change of polarity in the carbon
α to the carbonyl group in the catalytic transformation to an
electrophilic metal carbene (Scheme 1).
Shortly thereafter Vicario8 and Lassaletta9 independently reported
using donor−acceptor substituted hydrazones as acyl anion
equivalents that undergo addition reactions with α,β-unsatu-
rated aldehydes or keto esters, respectively, at the hydrazone
carbon instead of at the conjugated hydrazone nitrogen. These
successful examples of umpolung transformations suggested
that reactions of metal enol carbenes with donor−acceptor di-
substituted hydrazones could have a different outcome than was
found with 2 in eq 1, forming 6 or 7 instead of 3 in dirhodium(II)-
catalyzed reactions (Scheme 2). This transformation and the sub-
sequent outcome from Lewis acid catalysis have been explored.
Scheme 1. Change in Polarity from Diazocarbonyl
Compounds to the Corresponding Metal Carbenes
RESULTS AND DISCUSSION
■
At the onset we enlisted methyl enoldiazoacetate 1a and donor−
acceptor substituted hydrazone 5a as substrates, and their rhodium
acetate catalyzed reaction rapidly underwent complete conversion
Increased attention has recently been given to enol diazoacetates,
where the generated metal enol carbene shows electrophilic
character at both the carbene and vinylogous positions and
preferential reaction occurs at the vinylogous position.5,6 In one
example of a vinylogous reaction we reported a stepwise [3 + 3]-
cycloaddition of enoldiazoacetates 1 with diarylhydrazones 2 in
Received: December 11, 2012
Published: January 9, 2013
© 2013 American Chemical Society
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Scheme 2. Umpolung with Donor−acceptor Substituted Hydrazones in Dirhodium(II)-Catalyzed Reactions of 1
to give 6a in 76% isolated yield.10 Although 6a was unstable
and decomposed slowly in dichloromethane, this product was
converted to pyrazole 8a efficiently when catalyzed by a Lewis
acid, and Sc(OTf)3 offered the best results with 89% isolated
yield (Scheme 3). The structure of the pyrazole product 8 was
Numerous methodologies have been reported for pyrazole
syntheses,14 and the Knorr condensation reaction of dicarbonyl
compounds is the most prevalent approach for pyrazole syn-
thesis.15 However, this classic condensation between α,γ-diketo
esters and hydrazines is hampered by low regioselectivity,16 and
general synthetic processes for functionalized pyrazoles having
structural diversity and complexity continue to be needed. With
the process that is described in Scheme 3 we present a versatile
cascade reaction to produce multifunctionalized pyrazoles by a
dirhodium(II)-catalyzed vinylogous umpolung reaction fol-
lowed by Lewis acid catalyzed cyclization and aromatization.
To test the generality of this cascade reaction, a series of
donor−acceptor substituted hydrazones was employed under
the same conditions. In all cases, the isolated yield of the
pyrazoles exceeded 70%, regardless of the electronic properties
and different substituents at the aryl group (Table 1, entries 1−6).
Scheme 3. Two-Step Conversion Compared to One-Pot
Two-Step Process
Table 1. Substrate Generality in the One-Pot Production of
a
the Pyrazoles
confirmed by single-crystal X-ray diffraction analysis of its chloro
derivative 8c (Figure 1).11 To increase reaction efficiency, we
b
entry
R1/R2 (1)
Ar in 5
8
yield of 8 (%)
1
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/Me (1a)
H/t‑Bu (1b)
H/Bn (1c)
Me/Me (1d)
Me/Me (1d)
Me/Bn (1e)
Et/Bn (1f)
4-MeOC6H4 (5a)
4-MeC6H4 (5b)
4-ClC6H4 (5c)
Ph (5d)
8a
8b
8c
8d
8e
8f
87
91
90
89
71
72
89
88
74
66
69
48
2
3
4
5
4-NO2C6H4 (5e)
2,4-Cl2C6H3 (5f)
4-MeOC6H4 (5a)
4-MeOC6H4 (5a)
4-MeOC6H4 (5a)
4-ClC6H4 (5c)
4-MeOC6H4 (5a)
4-MeOC6H4 (5a)
6
7
8g
8h
8i
8
9
10
11
12
8j
8k
8l
a
Reactions were carried out on a 0.5 mmol scale: 1 (0.6 mmol), 5 (0.5
mmol), 4 Å MS (100 mg), in 3.0 mL of DCM with Rh2(OAc)4 (2.0
mol %) at room temperature; then Sc(OTf)3 (5.0 mol %) was added
b
and stirred at room temperature overnight. Isolated yield of 8 based
on limiting reagent 5.
Figure 1. Crystal structure of 8c.
In addition, changing the ester alkyl group of the enoldiazoacetate
(R2) from methyl to tert-butyl and benzyl gave the same
product yields (entries 1, 7, and 8), but substituents other than
hydrogen at the vinylogous position (R1) lowered the product
yield by about 10% on going from hydrogen to methyl and an
additional 20% by changing from methyl to ethyl (entries 9, 11,
and 12). Reactions with more sterically bulky substrates (e.g.,
enoldiazoacetate with R1 = Ph or the donor−acceptor sub-
stituted hydrazone derived from ethyl 2-oxopropanoate) showed
only decomposition of the diazo compound.
carried out the two-step process in one pot since both of the
reactions are carried out in dichloromethane. By adding Sc(OTf)3
directly into the reaction mixture at room temperature imme-
diately after complete conversion to 6a, pyrazole product 8a
was smoothly generated in high yield (87% isolated yield from 5a),
which avoided unnecessary losses from isolation of intermediate 6.
The pyrazole scaffold is well-represented in bioactive struc-
tures.12 Pyrazoles having a functionality installed at the C-3 or
C-5 position have attracted a significant amount of attention.13
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The proton transfer step of the hydrazone carbon-centered
vinylogous addition was further studied by using deuterium-
labeled hydrazone 5a in reactions with enol diazoacetate 1a.
Deuterium was found to reside exclusively on the carbon α to
the carboxylate ester in the pyrazole product 8a formed between
1a and 5a. However, with vinyl-substituted enoldiazoacetate 1d
(R1 = Me) in this reaction, only 65% of the deuterium was found
in the final pyrazole product 8i (Scheme 4). These diverse results
diastereoisomer (Scheme 6)19 and was smoothly converted to
pyrazole 8i in high yield under the same conditions as was
Scheme 6
Scheme 4. Labeling Experiments Define Outcome of
Vinylogous Addition Step
prompted us to look at the intermediates of the vinylogous
addition step (6a and 7i), and 2D-SHQC NMR analysis showed
that these two isolated compounds possessed different structures:
6a had a C−N double bond, while 7i had a N−N double bond.17
The loss of deuterium in forming pyrrazole product 8i was
rationalized as due to proton shifts in reaction intermediates as
shown in Scheme 5, although alternative hydrazone N−H
reported with Sc(OTf)3 in Table 1. The base-promoted reac-
tion is consistent with a mechanism through which the hydra-
zone anion undergoes intramolecular Michael addition, and this
pathway differs from that of the conventional pyrazole synthsis
via the Knorr condensation reaction, in which a hydrazine
anion directly attacks the carbonyl carbon.20 Support for this
proposalthat of Michael addition instead of attack on the
carbonyl group formed by hydrolysis of the vinyl silyl ether
comes from the reaction of the hydrazone derivative 15, which
was formed as a byproduct from the Sc(OTf)3-catalyzed reac-
tion of 7; compound 15 has the same structural framework as
the intermediate of the Knorr reaction.16d This byproduct (15)
did not form the pyrazole product under standard Lewis acid
conditions with Sc(OTf)3 (Table 1) even after treatment for
24 h, and only with trifluoroacetic acid did conversion to 8j
occur.
Scheme 5. Possible Pathways for Deuterium Retention/Loss
In conclusion, we have developed a regiospecific cascade
transformation that enables the efficient preparation of multi-
functional pyrazoles starting from enol diazoacetates and donor−
acceptor substituted hydrazones in good to high overall yields. The
sequence of reactions is triggered by Rh(II)-catalyzed dinitrogen
extrusion from enol diazoacetates to form the substrate-dependent
intermediates with a C−N (6) or N−N (7) double bond followed
by Lewis acid promoted direct addition and aromatization.
Although many nucleophilic addition reactions to vinylogous
positions have been reported, this is the rare example using the
hydrazone’s “C” instead of “N” for vinylogous reactivity. Further
expansions of vinylogous reactions with enol diazoacetates are
being pursued.
insertion at the metal carbene center followed by an aza-[3,3]-
sigmatropic rearrangement cannot be ruled out. Kinetically
controlled 1,4-H and 1,6-D shifts of the vinylogous addition
intermediate 9,18 dependent on the acidity of the proton
adjacent to the carboxylate group, give 10 and 11, respectively,
and 10 is prone to deuteron−proton exchange (from 10 to 12)
with further loss occurring during cyclization and aromatization.
Further investigation of the cyclization step using base
instead of Lewis acid with the reaction mixture from 1d and 5
that contained azo compound 7 demonstrated that the enol
carbene generated vinylogous addition product can be con-
verted to the ring-closed product through catalysis by sodium
hydroxide in ethanol at room temperature. The cyclized pyrazole
precursor 14 was formed in 59% isolated yield as only one
EXPERIMENTAL SECTION
■
General Information. Reactions were performed in oven-dried
(140 °C) glassware under an atmosphere of dry N2. Dichloromethane
(DCM) was passed through a solvent column prior to use and was
kept over 3 Å molecular sieves. Thin-layer chromatography (TLC) was
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carried out using silica gel plates. The developed chromatogram was
analyzed by a UV lamp (254 nm). Liquid chromatography was per-
formed using flash chromatography of the indicated system on silica
and hydrazone 5 (0.50 mmol) in dichloromethane (2.0 mL) was
added enol diazoacetate 1 (0.60 mmol) in dichloromethane (1.0 mL)
over 1 h via a syringe pump at 0 °C. The reaction solution was stirred
for another 2 h at room temperature followed by adding solid
Sc(OTf)3 (5.0 mol %) directly into the reaction mixture and was
stirred overnight under the same conditions. The crude reaction
mixture was purified by column chromatography on silica gel (eluent
hexanes/EtOAc 3/1 to 1/1) to give the pure pyrazole 8 in good to
high yield.
Ethyl 5-(2-Methoxy-2-oxoethyl)-1-(4-methoxyphenyl)-1H-pyra-
zole-3-carboxylate (8a). Yellow oil. 138 mg (0.44 mmol), 87%
yield. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.33 (d, J = 9.0 Hz, 2H),
6.96 (d, J = 9.0 Hz, 2H), 6.90 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.84
(s, 3H), 3.66−3.65 (comp, 5H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): 169.3, 162.4, 160.2, 144.0, 137.5, 131.6, 127.6,
114.4, 109.9, 61.1, 55.7, 52.6, 32.0, 14.5. HRMS (ESI): m/z calcd for
C16H19N2O5 [M + H]+ 319.1288, found 319.1278.
Ethyl 5-(2-Methoxy-2-oxoethyl)-1-(p-tolyl)-1H-pyrazole-3-car-
boxylate (8b). Yellow oil. 137 mg (0.46 mmol), 91% yield.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.30 (d, J = 8.2 Hz, 2H),
7.25 (d, J = 8.2 Hz, 2H), 6.91 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.68
(s, 2H), 3.65 (s, 3H), 2.40 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): 169.3, 162.4, 144.1, 139.4, 137.4, 136.2, 129.9,
126.0, 110.1, 61.1, 52.6, 32.0, 21.3, 14.5. HRMS (ESI): m/z calcd for
C16H19N2O4 [M + H]+ 303.1339, found 303.1348.
1
gel (230−400 mesh). H NMR and 13C NMR spectra were recorded
in CDCl3 on a 400 MHz spectrometer; chemical shifts are reported
in ppm with the solvent signals as reference, and coupling constants
(J) are given in Hertz. The peak information is described as follows:
br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, comp = composite. High-resolution mass spectra (HRMS)
were performed on a TOF-CS mass spectrometer using CsI as the
standard. Dirhodium tetraacetate, scandium(III) triflate, and other
Lewis acids were obtained commercially and used as received. Enol
diazoacetates 121 were synthesized according to literature procedures.
Hydrazones 5 were synthesized as described.8
General Procedure for the Preparation of Hydrazones 5. A
suspension of aryl hydrazine hydrochloride (14.0 mmol) in anhydrous
THF (20.0 mL) was treated with triethylamine (2.0 mL, 14.0 mmol)
before a solution of ethyl glyoxylate (50% solution in toluene, 2.9 mL,
14.5 mmol) was added dropwise into the reaction mixture at 0 °C.
The mixture was stirred at this temperature for 30 min and then for
12 h at room temperature. The reaction mixture was then filtered
under vacuum to collect the triethylamine hydrochloride salt. The
filtrates were concentrated under reduced pressure, and the resulting
solid was dissolved in dichloromethane (30 mL) and then washed with
1 M HCl (20 mL) and water (2 × 20 mL). The resulting organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced
pressure to produce the desired hydrazone 5, which was further puri-
fied by recrystallization from ether before use.
Ethyl 1-(4-Chlorophenyl)-5-(2-methoxy-2-oxoethyl)-1H-pyrazole-
3-carboxylate (8c). White solid, mp 109−110 °C. 145 mg
(0.45 mmol), 90% yield. 1H NMR (400 MHz, CDCl3): δ (ppm)
7.44 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 6.90 (s, 1H), 4.38
(q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 3.65 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): 169.1, 162.2, 144.5, 137.4, 137.2,
135.2, 129.6, 127.3, 110.5, 61.2, 52.6, 31.9, 14.4. HRMS (ESI): m/z
calcd for C15H16ClN2O4 [M + H]+ 323.0793, found 323.0799.
Ethyl 5-(2-Methoxy-2-oxoethyl)-1-phenyl-1H-pyrazole-3-carbox-
General Procedure for the Dirhodium-Catalyzed Reactions.
To an oven-dried flask containing a magnetic stirring bar, 4 Å mole-
cular sieves (100 mg), Rh2(OAc)4 (2.0 mol %), and hydrazone 5
(0.50 mmol) in dichloromethane (2.0 mL) was added enol dia-
zoacetate 1 (0.60 mmol) in dichloromethane (1.0 mL) over 1 h via a
syringe pump at 0 °C. The solvent was evaporated under reduced
pressure, and the residue was purified by column chromatography on
silica gel (eluent hexanes/EtOAc 50/1 to 30/1) to give the pure product
6 or 7.
1
ylate (8d). Yellow oil. 128 mg (0.45 mmol), 89% yield. H NMR
(400 MHz, CDCl3): δ (ppm) 7.48−7.42 (comp, 5H), 6.93 (s, 1H),
4.41 (q, J = 7.1 Hz, 2H), 3.70 (s, 2H), 3.65 (s, 3H), 1.39 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): 169.2, 162.4, 144.3, 138.7, 137.4,
129.4, 129.3, 126.1, 110.2, 61.2, 52.6, 32.0, 14.5. HRMS (ESI): m/z
calcd for C15H17N2O4 [M + H]+ 289.1183, found 289.1172.
Ethyl 5-(2-Methoxy-2-oxoethyl)-1-(4-nitrophenyl)-1H-pyrazole-3-
carboxylate (8e). Yellow solid, mp 124−126 °C. 118 mg
(0.36 mmol), 71% yield. 1H NMR (400 MHz, CDCl3): δ (ppm)
8.39 (d, J = 9.1 Hz, 2H), 7.75 (d, J = 9.1 Hz, 2H), 6.99 (s, 1H), 4.45
(q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.72 (s, 3H), 1.42 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): 169.0, 162.0, 147.7, 145.6, 134.8,
137.6, 126.4, 125.0, 111.7, 61.6, 53.0, 32.2, 14.6. HRMS (ESI): m/z
calcd for C15H16N3O6 [M + H]+ 334.1034, found 334.1031.
(2Z,5E)-6-Ethyl 1-Methyl 3-[(tert-Butyldimethylsilyl)oxy]-5-[2-(4-
methoxyphenyl)hydrazono]hex-2-enedioate (6a). Yellow oil. 100%
1
conversion, 170 mg (0.38 mmol), 76% yield. H NMR (400 MHz,
CDCl3): δ (ppm) 8.18 (bs, 1H), 7.15 (d, J = 9.0 Hz, 2H), 6.85
(d, J = 9.0 Hz, 2H), 5.03 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.77
(s, 3H), 3.60 (s, 3H), 3.49 (s, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.01
(s, 9H), 0.31 (s, 6H). 13C NMR (100 MHz, CDCl3): 165.5, 165.0,
160.5, 155.6, 136.9, 128.6, 115.7, 114.8, 99.1, 61.5, 55.7, 50.8, 33.9,
25.9, 18.7, 14.5, −3.9. HRMS (ESI): m/z calcd for C22H35N2O6Si
[M + H]+ 451.2259, found 451.2231.
(Z)-6-Ethyl 1-Methyl 3-[(tert-Butyldimethylsilyl)oxy]-5-[(E)-(4-
methoxyphenyl)diazenyl]-4-methylhex-2-enedioate (7i). Yellow
oil. 100% conversion, 193 mg (0.42 mmol), 83% yield. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.74 (d, J = 9.0 Hz, 2H), 6.96 (d, J =
9.0 Hz, 2H), 5.12 (s, 1H), 5.52 (d, J = 7.3 Hz, 1H), 4.62−4.21 (comp,
2H), 3.87 (s, 3H), 3.63 (s, 3H), 3.34−3.27 (m, 1H), 1.29−1.26
(comp, 6H), 1.03 (s, 9H), 0.31 (s, 3H), 0.29 (s, 3H). 13C NMR
(100 MHz, CDCl3): 169.6, 168.0, 165.9, 162.4, 146.3, 124.9, 114.2,
98.9, 81.3, 61.6, 55.8, 50.8, 44.0, 26.2, 18.9, 15.4, 14.4, −3.6, −3.7.
HRMS (ESI): m/z calcd for C23H37N2O6Si [M + H]+ 465.2415, found
465.2443.
General Procedure for the Lewis Acid Catalyzed Pyrazole
Synthesis (Method A). To an oven-dried flask containing a magnetic
stirring bar, Lewis acid (5.0 mol %) and 6 or 7 (0.30 mmol) in di-
chloromethane (2.0 mL) were stirred for 3 h (or as indicated) at room
temperature. Once the diazo compound was consumed (determined
by TLC, eluent hexanes/EtOAc 2/1, Rf(material) ≈ 0.8, Rf(product)
≈ 0.1), the reaction mixture was purified by column chromatography
on silica gel (eluent hexanes/EtOAc 3/1 to 1/1) to give the pure
pyrazole 8 in high yield.
Ethyl 1-(2,4-Dichlorophenyl)-5-(2-methoxy-2-oxoethyl)-1H-pyra-
zole-3-carboxylate (8f). White solid, mp 81−82 °C. 128 mg (0.36
mmol), 72% yield. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.54
(s, 1H), 7.43−7.37 (m, 2H), 6.94 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H),
3.70−3.44 (comp, 5H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): 168.7, 162.1, 145.2, 138.8, 136.9, 134.9, 133.3, 131.2, 130.2,
128.2, 109.8, 61.3, 52.6, 31.6, 14.5. HRMS (ESI): m/z calcd for C15H15
Cl2N2O4 [M + H]+ 357.0403, found 357.0433.
Ethyl 5-[2-(tert-Butoxy)-2-oxoethyl]-1-(4-methoxyphenyl)-1H-
pyrazole-3-carboxylate (8g). Yellow oil. 160 mg (0.45 mmol), 89%
yield. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.36 (d, J = 9.0 Hz, 2H),
6.96 (d, J = 9.0 Hz, 2H), 6.89 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.84
(s, 3H), 3.57 (s, 2H), 1.40−1.33 (comp, 12H). 13C NMR (100 MHz,
CDCl3): 168.1, 162.0, 160.1, 143.9, 138.2, 131.9, 127.6, 114.4, 109.8,
82.2, 61.1, 55.8, 32.5, 28.0, 14.6. HRMS (ESI): m/z calcd for
C19H25N2O5 [M + H]+ 361.1758, found 361.1779.
Ethyl 5-[2-(Benzyloxy)-2-oxoethyl]-1-(4-methoxyphenyl)-1H-pyr-
azole-3-carboxylate (8h). Yellow oil. 173 mg (0.44 mmol), 88% yield.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.37−7.29 (comp, 7H), 6.94
(s, 1H), 6.91 (d, J = 9.0 Hz, 2H), 5.12 (s, 2H), 4.43 (q, J = 7.1 Hz,
2H), 3.85 (s, 3H), 3.72 (s, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): 168.8, 162.5, 160.2, 144.0, 137.5, 135.3, 131.7,
128.8, 128.7, 128.6, 127.7, 114.5, 110.1, 67.4, 61.2, 55.8, 32.3, 14.6.
General Procedure for Pyrazole Synthesis in One Pot
(Method B, Table 1). In an oven-dried flask containing a magnetic
stirring bar, 4 Å molecular sieves (100 mg), Rh2(OAc)4 (2.0 mol %),
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HRMS (ESI): m/z calcd for C22H23N2O5 [M + H]+ 395.1601, found
395.1617.
(d, J = 7.2 Hz, 3H), 0.84 (s, 9H), 0.10 (s, 3H), −0.09 (s, 3H). 13C
NMR (100 MHz, CDCl3): 169.7, 162.4, 157.0, 144.3, 134.2, 123.4,
114.1, 98.1, 61.2, 55.7, 52.0, 50.4, 39.3, 25.8, 15.3, 14.6, −2.9, −3.9.
HRMS (ESI): m/z calcd for C23H37N2O6Si [M + H]+ 465.2415, found
465.2442.
Ethyl 5-(2-Methoxy-2-oxoethyl)-1-(4-methoxyphenyl)-4-methyl-
1H-pyrazole-3-carboxylate (8i). Yellow solid, mp 107−108 °C. 123
1
mg (0.37 mmol), 74% yield. H NMR (400 MHz, CDCl3): δ (ppm)
7.34 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.42 (q, J = 7.1 Hz,
2H), 3.85 (s, 3H), 3.67 (s, 3H), 3.61 (s, 2H), 2.31 (s, 3H), 1.41
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 169.5, 163.3, 160.2,
141.6, 135.4, 132.0, 127.7, 120.0, 114.4, 60.8, 55.8, 52.6, 30.6, 14.6, 9.5.
HRMS (ESI): m/z calcd for C17H21N2O5 [M + H]+ 333.1445, found
333.1425.
General Procedure for the Synthesis of Pyrazole 8j from 15.
This ketone precursor 15 was isolated as a byproduct in 16% yield
from the reaction of 1d with 5c under the conditions of method B. In
an oven-dried flask containing a magnetic stirring bar and 15 (28.0 mg,
0.08 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic
acid (TFA, 1 drop) at room temperature. The reaction gave 100%
conversion to the corresponding pyrazole 8j in 96% isolated yield after
stirring overnight under these conditions.
Ethyl 1-(4-Chlorophenyl)-5-(2-methoxy-2-oxoethyl)-4-methyl-
1H-pyrazole-3-carboxylate (8j). Yellow solid, mp 106−108 °C. 111
1
mg (0.33 mmol), 66% yield. H NMR (400 MHz, CDCl3): δ (ppm)
(E)-1-Ethyl 6-Methyl 2-[2-(4-Chlorophenyl)hydrazono]-3-methyl-
4-oxohexanedioate (15). Yellow solid, mp 92−93 °C. 28 mg, 16%
7.48 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H), 4.45 (q, J = 7.1 Hz,
2H), 3.71 (s, 3H), 3.66 (s, 2H), 2.34 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3): 169.3, 163.1, 142.4, 137.7, 135.24,
1
yield. H NMR (400 MHz, CDCl3): δ (ppm) 12.24 (bs, 1H), 7.27
(d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H),
3.96 (q, J = 7.0 Hz, 1H), 3.57 (s, 3H), 3.56−3.52 (comp, 2H), 1.42−
1.35 (comp, 6H). 13C NMR (100 MHz, CDCl3): 200.0, 167.8, 163.0,
141.8, 129.5, 127.6, 127.1, 115.3, 61.6, 52.5, 50.2, 47.5, 14.6, 14.2.
HRMS (ESI): m/z calcd for C16H20ClN2O5 [M + H]+ 355.1055,
found 355.1058.
135.18, 129.7, 127.6, 120.6, 61.1, 52.8, 30.7, 14.7, 9.5. HRMS (ESI):
m/z calcd for C16H18ClN2O4 [M + H]+ 337.0950, found 337.0977.
Ethyl 5-[2-(Benzyloxy)-2-oxoethyl]-1-(4-methoxyphenyl)-4-meth-
yl-1H-pyrazole-3-carboxylate (8k). White solid, mp 111−112 °C. 141
1
mg (0.34 mmol), 69% yield. H NMR (400 MHz, CDCl3): δ (ppm)
7.35 (comp, 7H), 6.89 (d, J = 9.0 Hz, 2H), 5.12 (s, 2H), 4.44
(q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 3.65 (s, 2H), 2.31 (s, 3H), 1.42
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): 168.9, 163.2, 160.1,
141.6, 135.5, 135.4, 132.0, 128.8, 128.7, 128.6, 127.8, 120.1, 114.4,
67.4, 60.9, 55.8, 30.9, 14.7, 9.5. HRMS (ESI): m/z calcd for
C23H25N2O5 [M + H]+ 409.1758, found 409.1772.
Ethyl 5-(2-(Benzyloxy)-2-oxoethyl)-4-ethyl-1-(4-methoxyphenyl)-
1H-pyrazole-3-carboxylate (8l). Yellow solid, mp 78−79 °C. 101 mg
(0.24 mmol), 48% yield. 1H NMR (400 MHz, CDCl3): δ (ppm)
7.39−7.29 (comp, 7H), 6.88 (d, J = 9.0 Hz, 2H), 5.11 (s, 2H), 4.44
(q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.65 (s, 2H), 2.76 (q, J = 7.5 Hz,
2H), 1.42 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H). 13C NMR
(100 MHz, CDCl3): 169.1, 163.0, 160.1, 141.1, 135.4, 134.9, 132.0,
128.8, 128.72, 128.68, 127.8, 126.5, 114.4, 67.4, 60.9, 55.7, 32.7, 17.6,
15.3, 14.6. HRMS (ESI): m/z calcd for C24H27N2O5 [M + H]+
423.1914, found 423.1911.
ASSOCIATED CONTENT
* Supporting Information
Text, figures, and CIF files giving NMR spectra of new compounds
and X-ray diffraction analysis data for 8c. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: mdoyle3@umd.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the support for this research from the
National Institutes of Health (GM 46503).
■
General Procedure for the Deuteration Reactions (Scheme
4). In an oven-dried flask containing a magnetic stirring bar and
hydrazone 5a (0.50 mmol) in DCM (2.0 mL) was added D2O (0.10
mL) at room temperature, and the deuteration experiment of 5a was
REFERENCES
1
■
monitored by H NMR (about 10 min, 5a(H)/5a(D) < 5/95). This
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General Procedure for the Synthesis of 14. In an oven-dried
flask containing a magnetic stirring bar, 4 Å molecular sieves (100 mg),
Rh2(OAc)4 (2.0 mol %), and hydrazone 5a (0.5 mmol) in di-
chloromethane (2.0 mL) was added enol diazoacetate 1d (0.6 mmol)
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another 2 h at room temperature, and after removal of the solvent
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Ethyl 5-[(tert-Butyldimethylsilyl)oxy]-5-(2-methoxy-2-oxoethyl)-
1-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxy-
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6.88 (d, J = 9.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H),
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