Catalyst-Free Rearrangement of Allenyl Aryldiazoacetates into 1,5-Dihydro-4H-pyrazol-4-ones

Article abstract of DOI:10.1021/acs.joc.6b01833

Phenylpropargyl diazoacetates exist in equilibrium with 1-phenyl-1,2-dien-1-yl diazoacetate - allenes that are rapidly formed at room temperature through 1,3-acyloxy migration catalyzed by gold(I) or gold(III) compounds, and these catalysts react solely with the π-donor rather than with the diazo group. The product allene of the aryldiazoacetates undergoes rearrangement that is not catalyzed by gold in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene, initiating a sequence of bond-forming reactions, resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. These 1,5-dihydro-4H-pyrazol-4-ones undergo intramolecular 1,3-acyl migration to form an equilibrium mixture and can quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. Reactions of phenylpropargyl phenyldiazoacetates catalyzed by cationic gold complexes are initiated at the diazo functional group to form a gold carbene whose subsequent cascade process (intramolecular addition, then aromatic substitution) results in the formation of a product that is uniquely characteristic of this pathway.

Full text of DOI:10.1021/acs.joc.6b01833

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Article
Catalyst-free Rearrangement of Allenyl
Aryldiazoacetates into 1,5-Dihydro-4H-pyrazol-4-ones
Kostiantyn O. Marichev, Huang Qiu, Austin C. Offield, Hadi Arman, and Michael P Doyle
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01833 • Publication Date (Web): 08 Sep 2016
Downloaded from http://pubs.acs.org on September 9, 2016
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The Journal of Organic Chemistry
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Catalystꢀfree Rearrangement of Allenyl Aryldiazoacetates
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into 1,5ꢀDihydroꢀ4Hꢀpyrazolꢀ4ꢀones
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Kostiantyn O. Marichev, Huang Qiu, Austin C. Offield, Hadi Arman, and Michael P. Doyle*
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United
States
Eꢀmail: michael.doyle@utsa.edu
ABSTRACT: Phenylpropargyl diazoacetates exist in equilibrium with 1ꢀphenylꢀ1,2ꢀdienꢀ1ꢀyl diazoacetate ꢀ
allenes that are rapidly formed at room temperature through 1,3ꢀacyloxy migration catalyzed by gold(I) or
gold(III) compounds, and these catalysts react solely with the πꢀdonor rather than with the diazo group. The
product allene of the aryldiazoacetates undergoes rearrangement that is not catalyzed by gold in which the
terminal nitrogen of the diazo functional group adds to the central carbon of the allene initiating a sequence of
bond forming reactions resulting in the production of 1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀones in good yields. These 1,5ꢀ
dihydroꢀ4Hꢀpyrazolꢀ4ꢀones undergo intramolecular 1,3ꢀacyl migration to form an equilibrium mixture and can
quantitatively transfer the acyl group to an external nucleophile with formation of 4ꢀhydroxypyrazoles. Reactions
of phenylpropargyl phenyldiazoacetates catalyzed by cationic gold complexes are initiated at the diazo functional
group to form a gold carbene whose subsequent cascade process (intramolecular addition then aromatic
substitution) results in the formation of a product that is uniquely characteristic of this pathway.
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INTRODUCTION
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Gold catalysis provides powerful methodologies for unique metalloꢀorganic transformations.1 Activation of
organic functional groups by gold(I) and gold(III) complexes initiates diverse pathways for often unique
reactions.2 One of the most useful of these transformations has been that of propargyl esters,3 which form allenes
by 1,3ꢀacyloxy migration, that undergo varied catalytic reactions and in the presence of weak bases are converted
to conjugated dienes.4 We have been intrigued with the reactions of propargyl diazoacetates because these
substrates contain two reactive centers for gold catalysts, and both are known to initiate reaction processes that
are characteristic of their requisite functional groups.2,5 In particular, the diazo functionality of a propargyl
phenyldiazoacetate is expected to react with the gold catalyst that functions as a metalloꢀσꢀbond acceptor to
displace dinitrogen through backꢀdonation and form a metal carbene. This metal carbene is proposed to undergo
intramolecular addition to the proximal carbonꢀcarbon triple bond to form a derivative metal carbene that
completes the domino transformation by electrophilic substitution into the aromatic nucleus of the original
aryldiazoacetate (Scheme 1).6,7 πꢀBondꢀforming reactions by gold catalysts that occur initially at the carbonꢀ
carbon triple bond proceed by nucleophilic addition, then 1,3ꢀacyloxy migration, to a goldꢀcoordinated allene8
from which an acylium ion intermediate9 may be the key to undetermined product(s). Both pathways are well
documented, although the product outcome of the πꢀbond initiated pathway is revealed here for the first time.
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Scheme 1. CatalystꢀDependent Divergence of Reaction Pathway Based on σꢀBond Association with a
Diazo Functional Group versus πꢀBond Association with an Alkyne.
RESULTS AND DISCUSSION
Selectivity. Initial assessment of gold catalysis was evaluated with propargyl aryldiazoacetates using cationic
gold(I) catalysts, including those formed from ligated gold(I) chloride and silver salts. Cationic gold catalysts are
wellꢀestablished σꢀbond acceptors with aryldiazoacetates,5 and they have been widely used for dinitrogen
extrusion reactions of diazo compounds that are reported to produce the corresponding gold carbenes. Catalytic
reactions of phenylpropargyl phenyldiazoacetate 1 with representative Au(I)+ catalysts formed the product from
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the carbeneꢀinitiated domino transformation 2 in good yield (Scheme 2). Complete conversion of the reactant
was observed at room temperature, and no other discernable product was identified. Each of the gold catalysts
was soluble in the reaction solution.
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Scheme 2. Domino Reaction of Propargyl Phenyldiazoacetate 1 Catalyzed by Cationic Gold(I).
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Neutral gold(I) and gold(III) compounds are reported to have varying influences on reactions with diazo and
alkyne functional groups.1,2,5 A survey of representative compounds for reactions with 1 at 20 °C revealed that
5 mol % of chloro(tetrahydrothiophene)gold(I) [AuCl(C4H8S)] catalyzed its complete conversion to three
discernable products in the highest yield (Scheme 3). The surprising conversion of 1 to 3 and 4 retained all of the
atoms of the reactant but gave extensive rearrangement, including the conversion of the reactant ester to product
1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀones.
Scheme 3. Products from Gold(I)ꢀCatalyzed Rearrangement of Phenylpropargyl Phenyldiazoacetate 1.
Compounds 3 and 4 were observed spectroscopically to be related as structural isomers, and the crystal
structure of 4 was obtained (Figure 1a) after its isolation from the reaction mixture. Recognition of 3 and 4 as
potential benzoyl transfer agents prompted us to convert 3 and 4, individually and as a mixture, quantitatively to
the same 4ꢀhydroxypyrazole 6 by treatment with nucleophilic bases that included hydrazines and amines (XꢀRay
structure of analog 6ʹ, Figure 1b). Compound 5, although present in very low yield, was confirmed by spectral
and chromatographic comparison with the previously characterized compound.10
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Examination of this reaction as a function of solvent did not provide any improvement in the product yield, but
did show significant variation in the 3:4 product ratios (see Supporting Information). To determine if this product
variation could be due to an equilibrium between 3 and 4 under the reaction conditions, the formation of 3 and 4
in DCE was followed as a function of time over ten days at room temperature with high product accountability,
and the results from this investigation (Figure 2) clearly show an equilibrium between 3 and 4.
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Figure 1. XꢀRay structures of 1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀone 4 and deacylation product 6ʹ with 50% thermal
ellipsoid probability.
Slow deacylation resulting in 6 complicates the overall picture, but conclusions can be drawn that compound 3
is the product of kinetic control at room temperature, and 4 is the product of thermodynamic control.
Figure 2. Time course for the formation of 3, 4, and 6 in DCE at 20 ⁰C. Yields were determined by 1H NMR and
HPLC analyses of the reaction mixture after selected periods of time using 1,3,5ꢀtrimethoxybenzene as the
internal standard; reported yields are the averages of two runs.
Experiments performed at higher temperatures (50 and 84 °C) are consistent with this interpretation.
Compound 4 is the major isomer even at lower conversions of diazo compound 1. At 50 °C the maximum total
yield of 3+4 is 81% at a 12 h reaction time, and the ratio 3:4 is 2:3; whereas at 84 °C the reaction is complete
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(total yield of 3+4 is 80%) after 6 h, and 3:4 is 1:1. Continuing the reaction further at these higher temperatures
leads to lower product yield as the result of deacylation, from which 4ꢀhydroxypyrazole 6 is formed.
Cationic gold(I) and the neutral chloro(tetrahydrothiophene)gold(I) catalysts are mutually exclusive for
product formation from reactions with 1. Both catalysts are active at room temperature, and their application
provides products from reactions at the diazo functional group [2 from cationic gold(I)] and the alkyne functional
group [3, 4, and 5 from AuCl(C4H8S)] in good yields. Neutral gold(I) chloride complexes having strongly
coordinating ligands (Table 1) show very low or negligible conversion of phenylpropargyl phenyldiazoacetate 1
under the same conditions, even to reaction times of three days.
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Table 1. Screening of Gold(I) and Gold(III) Catalysts in Reactions with Phenylpropargyl Phenyldiazoacetate 1.
Conversion (%) Yield (%) Yield (%) Ratio Yield (%)
Entrya
Gold Catalyst
Temp (°C)
1
2b
3+4b
3:4b
5b
1
2
3
4
5
AuCl(IPr)
AuCl(CO)
84d (20)
84 (20)
84c (20)
84c (20)
84c (20)
68 (<5)
>95 (14)
40 (<5)
35 (<5)
45 (<5)
46
16 (9)
25
̶
̶
̶
14
47:53
9
3
̶
AuCl[P(OMe)3]
AuCl(PPh3)
AuCl(PMe3)
̶
̶
23
̶
̶
20
8
40:60
6
6
84c (20)
70 (<5)
57
̶
̶
̶
7
AuCl(C4H8S)i
AuCl(C4H8S)
AuCl(Me2S)
AuCl(Me2S)
20
84
20
84
20
84
20
84
>95
>95
>95
>95
>95
>95
>95
>95
̶
76
80
42
46
21
14
25
18
75:25
45:55
62:38
45:55
50:50
40:60
60:40
45:55
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4
8
̶
9
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̶
̶
3
10
11e
12f
13g
14h
5
j
AuPicCl2
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18
35
39
j
AuPicCl2
AuCl3(Pyridine)j
AuCl3(Pyridine)j
aReactions were performed on 0.10 mmol scale: a solution of 1 (0.10 mmol) in DCE (1.0 mL) was added to a
solution of Auꢀcatalyst (5 mol %) in DCE (1.0 mL) under a nitrogen atmosphere at 20 °C (% conversion in
parenthesis for entries 1ꢀ6) or in refluxing DCE, and the resulting reaction mixture was stirred for defined
b
1
periods of time. Conversion of 1, yields of 2, (3+4), 5, and ratios 3:4 were determined by H NMR analysis of
characteristic peaks using 2,4,6ꢀtrimethoxybenzene as the internal standard. Reaction times were 72 h for the
c
d
e
f
reactions carried out at 20 °C, and 6 h at 84 °C. Reaction times: 12 h; 48 h. Yield of product 6: 24%; 27%;
g32%; h38%. iAt 50 °C after 12 h: 81% yield of 3+4 with 3:4 = 40:60. jReduction of the catalyst to elemental gold
is significant.
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However, heating these complexes to the temperature of refluxing 1,2ꢀdichloroethane for up to 48 h gives 2
exclusively or as the major product (entries 1ꢀ6), albeit usually with low product yield and, generally, low %
conversion.11 The dimethylsulfide coordinated AuCl (entries 9ꢀ10) is not as effective a catalyst as its
tetrahydrothiophene analog (entries 7ꢀ8) with product yields only about half those found with AuCl(C4H8S).
Gold(III) catalysts (entries 11−14) are also less efficient than the AuCl(R2S) catalysts in the formation of
compounds 3 and 4. However, diene 5 is formed in the presence of these catalysts in yields up to 39%, and there
is no evidence for the formation of 2. In separate experiments we have established that the dimethylsulfide ligand
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of AuCl remains on Au(I) throughout the reaction; also, analysis by H NMR spectroscopy shows no apparent
association of AuCl(Me2S) with the diazo functional group of methyl phenyldiazoacetate at room temperature,
and <5% diazo decomposition occurred over 24 h.
Role of Allene. Close examination of the reaction process by NMR spectroscopy revealed that the key
transformation in the formation of 3 and 4 was the generation of allene (Scheme 1), which occurred within 5 min
at 20 °C. For these investigations the dimethyl analog (7) of cyclopentylpropargyl phenyldiazoacetate 1 was used
(Eq 1) to assess the course of the reaction. Allene 8 formation, which occurs by 1,3ꢀacyloxy transfer, begins to
take place immediately upon addition of the catalyst [5 mol % AuCl(Me2S) or AuCl(C4H8S)] as the only reaction
product, and reaches an apparent equilibrium (7:8 = 45:55 with either catalyst).
With added gold catalyst up to 2 equiv. based on 7 no further change in the 7:8 ratio occurred. Confirmation of
this process was made with phenyldimethylpropargyl benzoate under the same conditions (allene:alkyne = 3:2)
and with 1 (allene:alkyne = 1:2). The validity of the reversibility of Au(I)ꢀcatalyzed [3,3]ꢀrearrangements of
propargylic esters has been reported,12 and with propargyl diazoacetates additional stabilization by the diazo
group of the cyclic carbocation intermediate on the pathway to allene formation could be expected. Furthermore,
when the allene was isolated from the reaction mixture free of gold catalyst, the allene was observed to undergo
slow conversion to the rearranged products corresponding to 3 and 4, but without any obvious formation of 5.
This conversion was first order in 7 with a rate constant of 1.05 × 10−5 sec−1 at 20 °C, and addition of
AuCl(Me2S) did not influence the reaction rate. The activation energy measured over 20−60 °C was
18.8 kcal/mol (R2 = 0.999) with ΔH‡ = 18.2 kcal/mol and ΔS‡ = −19.4 cal/degꢀmol at 298 K.
Reaction Mechanism. A stepwise mechanism for the neutral gold(I)ꢀcatalyzed rearrangement of arylpropargyl
aryldiazoacetate 9 is given in Scheme 4. Consistent with the reported allene formation in related propargyl
systems,13 the AuCl(R2S) catalyzed 1,3ꢀacyloxy rearrangement of 9 produces carboxyallene C that undergoes a
unique rearrangement between allene C and the diazo functional group to form the observed 3 directly in a
concerted fashion or stepwise through intermediate D. The rearrangement of C to 10 is a rare example of a diazo
compound reacting as an Nꢀelectrophile,14 and the only one that involves an allene. Diene 12 is formed from
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goldꢀactivated carboxyallene A, presumably through goldꢀcoordinated acylium ion intermediate B. Compound 10
is formed initially from A and undergoes acyl migration to reach equilibrium with 11. This mechanism explains
the formation of 10 from carboxyallene C, the equilibrium that exists between 10 and 11, and the formation of
only (Z)ꢀdiene 12 from A through B without evidence for the formation of the isomeric (E)ꢀdiene that was
reported when the same reaction is performed in the presence of 4ꢀchloropyridineꢀNꢀoxide.10,15
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Scheme 4. Proposed Mechanism for the Formation of 10, 11, and 12 from 9.
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The formation of 12 is consistent with the results reported for the rearrangement of an acetate analog of 1,9c
and the conversion of B to 12 is consistent with the formation of diene 12 as the sole geometrical isomer. The
difference between the two pathways for diene formation (in the presence and absence of pyridineꢀNꢀoxide) is
that the pyridineꢀNꢀoxide intercepts activated allene A as a base to form both (E)ꢀ and (Z)ꢀ12, whereas, without
the added base, B is formed and undergoes intramolecular proton transfer to form the observed (Z)ꢀ12.
Although diazo compounds are normally regarded as nucleophiles, with both the diazo carbon and the terminal
nitrogen as nucleophilic centers,16 there are examples in which the terminal nitrogen atom of diazo compounds
exhibits electrophilic reactivity.14b,17 These reactions are intermolecular and involve obvious nucleophilic attack
on the terminal nitrogen of diazocarbonyl compounds and result in the formation of hydrazone derivatives. The
formation of 10 can be considered to be initiated by intramolecular electrophilic addition of the Nꢀterminus of the
aryldiazoacetates onto the central carbon of the allene that is continued with hydrogen transfer and C4ꢀC2 bond
formation, which occurs with the release of the Ar2CO acyl group. To confirm that the allene forms both (Z)ꢀ and
(E)ꢀdienes with a pyridineꢀNꢀoxide, the latter undergoing [4+2]ꢀcycloaddition,10 propargyl phenyldiazoacetate 1
was combined with 1.1 equiv of 4ꢀchloropyridineꢀNꢀoxide and heated at 60 °C in the presence of 5 mol %
AuCl(C4H8S) for 6 h. Allene formation was observed prior to addition of 4ꢀchloropyridineꢀNꢀoxide, and both the
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(Z)ꢀdiene 5 and the cycloaddition product from the (E)ꢀdiene were the sole reaction products (Scheme 5). Diene
formation is not observed in the absence of gold(I) catalyst, but with only 20 mol % of 4ꢀchloropyridineꢀNꢀoxide
all four products (3, 4, (Z)ꢀ5 and (E)ꢀ5) were obtained from the reaction performed with 5 mol % AuCl(C4H8S) at
60 °C for 6 h.18
1
2
3
4
5
6
7
Scheme 5. Role of the PyridineꢀNꢀoxide in Diene Formation from Phenylpropargyl Phenyldiazoacetate 1.
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Substrate Scope. The substrate scope of phenylpropargyl aryldiazoacetates 9a─k (Table 2) demonstrates that
the AuCl(C4H8S)ꢀcatalyzed reaction is broadly appropriate for the synthesis of the 1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀ
ones 10 and 11, and these reactions are tolerant of both electronꢀdonating and electronꢀwithdrawing substituents
in the aryl group of the aryldiazoacetate. High total yields of the 10+11 composites are observed, and their 10:11
ratio is near 3:1 (Table 2). Substrate 9j with a 12ꢀmembered ring gives a high yield of the 10j+11j composite, but
its 10:11 ratio is 3:2. Tetrahydropyranyl derivatives 10k+11k are obtained in only 46% yield and a 78:22 10:11
ratio.
Table 2. Substrate Scope of Gold(I)ꢀCatalyzed Reaction of Phenylpropargyl Aryldiazoacetates 9.a
Ar (Y = CH2)
Yield (%)b, c
Ratio 10:11b
9−11
a
b
c
d
e
f
C6H5
76
75
85
78
87
83
73
75:25
72:28
72:28
88:12
85:15
83:17
70:30
pꢀMeOꢀC6H4
pꢀMeꢀC6H4
pꢀPhꢀC6H4
pꢀBrꢀC6H4
pꢀClꢀC6H4
pꢀCF3ꢀC6H4
g
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h
2ꢀC4H3Sd
67
88:12
1
2
3
Y (Ar = C6H5)
Yield (%)b, c
Ratio 10:11b
9−11
4
5
6
7
8
i
j
(CH2)2
(CH2)8
CH2O
73
86
46
78:22
59:41
78:22
k
9
10
11
12
aReactions were carried out at 20 °C on a 0.20 mmol scale: a solution of 1 in 2.0 mL DCE was added to a 5
mol % solution of AuCl(C4H8S) in 2.0 mL DCE under a nitrogen atmosphere, and the resulting reaction mixture
was stirred for 72 h. bRatios and yields were determined by 1H NMR spectroscopy using 2,4,6ꢀ
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trimethoxybenzaldehyde as the internal standard. Individual compounds 10 and 11 were isolated and fully
characterized (see Experimental Section and SI). d2ꢀC4H3S = 2ꢀThiophene.
With substrates having electronꢀwithdrawing or electronꢀdonating groups (EWG or EDG) in both arene nuclei,
the product outcome is quite similar (Scheme 6) to those presented in Table 2. However, having an EWG as Z
and an EDG as X (compound 9o) results in a lower yield of 10o+11o (47%) but a higher 10:11 ratio of 89:11.
High yield (79%) and almost exclusive formation of compound 10q (10:11 = 91:9) are observed from the
dimethyl analog 9q, whereas aryl unsubstituted analog 9p results in lower yield of 10p+11p (68%) with a 88:12
10:11 ratio.
Scheme 6. Substrate Scope of Gold(I)ꢀCatalyzed Reaction of Arylpropargyl Aryldiazoacetates 9.
The cyclobutyl analog 9r (Scheme 7) forms neither 10 nor 11. Instead, treatment of 9r with 5 mol %
AuCl(C4H8S) affords 13 in good yield (70%), but only at 80 °C over 12 h. This product is consistent with initial
formation of a goldꢀcarbene intermediate through the diazo functional group. The alternate pathway through a
strained allene intermediate is apparently too restrictive and, although the initial step in the 1,3ꢀacyl
rearrangement that produces the stabilized intermediate E is favorable, release of the C−O bond to form the
allene does not occur.
Scheme 7. Outcome of Gold(I)ꢀCatalyzed Reaction of Cyclobutyl Propargyl Reactant 9r.
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Diazoacetate Influence. The conversion of A to 10 in Scheme 4 was expected to be dependent on the relative
basicity of the ester carbonyl for 1,3ꢀacyl transfer and the relative electrophilicity of the diazo terminal nitrogen
for rearrangement. To evaluate these dependencies we prepared acceptor and acceptorꢀacceptor analogues (14
and 15) of the donorꢀacceptor phenylpropargyl aryldiazoacetate 9, as well as another donorꢀacceptor diazo
compound 16, and performed goldꢀcatalyzed reactions with them (Schemes 8a and 8b) under the same conditions
as those performed with 1 (see Table 1).
Scheme 8a. Product Dependence on Diazo Compound Catalyzed by AuCl(C4H8S).
Scheme 8b. Product Dependence on Diazo Compound Catalyzed by AuPicCl2.
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The Journal of Organic Chemistry
In all cases the allene intermediate was formed and reached equilibrium within 5 min, but the rearrangement
product 22 was not observed (Scheme 9). In contrast to reactions with propargyl aryldiazoacetates 1 or 9,
however, both 14 and 15 were unreactive with AuCl(C4H8S) at room temperature but in refluxing 1,2ꢀ
dichloroethane underwent cleavage to form enone 17 (Scheme 8a), whose formation is consistent with the
pathway through intermediate B in Scheme 4 (equivalent to F in Scheme 9), and with 18, the acidꢀcatalyzed
elimination product for which the diazoacetic acid is the leaving group. The absence of rearranged product 22 in
reactions with 14 or 15 can be attributed to the diminished electrophilicity of their diazo terminal nitrogens, but
the facility with which donorꢀacceptor diazo compound 16 forms cleavage product 17 instead of 22 is possibly
related to other factors.
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With the gold(III) catalyst AuPicCl2 the same reactions occurred with diazo compounds 14−16 (Scheme 8b)
but at lower temperatures and, except for 14, gave the same products as with AuCl(C4H8S). Diazoacetoacetate 14
gave diene 21 as the major product whose formation through intermediate F occurs in competition with the
production of cleavage product 17. Once again, the rearranged product 22 or its acyl transfer product is absent in
the product mixture, suggesting the uniqueness of the overall process that forms 22 and its analogues.
Scheme 9. Diazo Compound Alternate Pathways to Product Formation.
N2
N2
N2
2
H
Me
2
2
OH
O
O
3
R
1
R
1
R
1
O
Me
CH2
1,5-shift
-[Au]
Me
O
5
O
5
Me
O
5
Ph
5
3
4
3
Me
3
-(RCN2CO)
H
Ph
4
4
4
[Au]
Ph
H
Ph
[Au]
17
21
G
F
N2
N2
N2
Me
2
O
Me
2
O
3
2
O
fast
1
1
R
[Au]
Me
3
R
R
1
Me
3
Me
4
4
O
5
O
O
Me
4
[Au]
5
5
[Au]
19
Ph
Ph
Ph
[Au]
20
E
Ph
O
O
Me
5
3
H
O
4
O
2
NH
Ph
R
Me
N
1
R
-(RCN2COOH)
Me
N2
22
[Au]
18
Ph
H
CONCLUSION
We have discovered a unique gold(I)ꢀcatalyzed rearrangement of propargyl aryldiazoacetates and a platform on
which catalytic activity of gold complexes can be assessed. Arylpropargyl aryldiazoacetates have two reactive
sites for reactions with gold complexes. If initial interaction occurs at the diazo carbon, a gold carbene is the
outcome, and a subsequent cascade process results in the formation of a product that is uniquely characteristic of
this pathway. If gold coordination occurs with the carbonꢀcarbon triple bond, 1,3ꢀacyloxy migration of the
propargylic ester promoted by the diazoester takes place. The corresponding allene formed rapidly is a stable
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intermediate, and it determines the course of subsequent processes, one of which is to undergo goldꢀcatalyzed
formation of a goldꢀacylacylium ion intermediate to form stable products by cleavage or intramolecular hydrogen
migration. Alternatively, the allene intermediate undergoes a complex transformation, not catalyzed by gold, in
which the terminal nitrogen of the diazo functional group adds at the central carbon of the allene to initiate a
sequence of bond forming reactions resulting in the production of 1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀones in good yields.
As acyl transfer agents these unique products undergo intramolecular 1,3ꢀacyl migration to form an equilibrium
mixture of two isomeric 1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀones under the reaction conditions or quantitatively transfer
the acyl group to an external nucleophile with formation of 4ꢀhydroxypyrazoles. Cationic gold(I) complexes
initiate their reactions at room temperature exclusively with the diazo functional group of propargyl
phenyldiazoacetates, whereas both AuCl(R2S) and gold(III) catalysts undergo initial reaction exclusively at the
carbonꢀcarbon triple bond. Neutral gold(I) chloride complexes having strongly coordinating ligands show very
low or negligible conversion of propargyl phenyldiazoacetates at room temperature, but they undergo slow
reaction at higher temperatures to give mainly the product from reaction at the diazo functional group, which
may have occurred after chloride dissociation,2c sometimes in competition with products from reaction at the
carbonꢀcarbon triple bond.
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EXPERIMENTAL SECTION
General Information. All reactions were carried out under an atmosphere of dry nitrogen in oven dried
glassware using freshly distilled solvents. All solvents were purified and dried using standard techniques. Thin
Layer Chromatography (TLC) analyses were performed on precoated analytical plates Silica Gel 60 F254, and
visualized with the use of UV light or iodine stain (I2 and Silica Gel 60). Highꢀresolution mass spectra (HRMS)
were performed on a microTOFꢀESI mass spectrometer. Exact masses were reported for the molecular ions
[M+Na]+, [M+H]+ or [M−H]−. Column chromatography was performed on a CombiFlash purification system
using normal phase disposable columns. IR spectra were recorded using a FTꢀIR spectrometer. NMR spectra
were recorded on spectrometers at 300, 400 or 500 MHz (1H NMR) and 76, 100 or 126 MHz (13C NMR).
Chemical shifts are reported in ppm using residue CHCl3 (δ 7.26 ppm)/H2O (δ 1.56 ppm), CH3OH (δ
1
3.31 ppm)/H2O (δ 4.87 ppm), DMSO (δ 2.50 ppm)/H2O (δ 3.33 ppm) for H NMR reference and the central
resonance of CDCl3 (δ 77.16 ppm), CD3OD (δ 49.00 ppm), DMSOꢀd6 (δ 39.52 ppm) for 13C NMR reference. 1H
NMR spectra are reported as follows (s = singlet, br = broad singlet, d = doublet, t = triplet, q = quartet, p =
pentet, m = unresolved multiplet, comp = composite of magnetically nonequivalent protons); coupling constants
(J) are given in Hertz (Hz).
Materials. AuCl(PPh3), AuCl(PMe3), AuCl[P(OMe)3], Chloro[2ꢀdicyclohexyl(2′,6′ꢀdimethoxybiphenyl)ꢀ
phosphine]ꢀgold(I), and AuPicCl2 were purchased from SigmaꢀAldrich; AuCl(C4H8S), AuCl(Me2S), AuCl(CO),
(IPr)AuCl, and AuCl3(Py) were purchased from Strem Chemicals. All other chemicals were obtained from
commercial sources and used as received without further purification.
Characterization of Propargyl Diazoacetates. Detailed procedures for the preparation of diazo compounds 9
and characterization data of compounds 1 (9a), 9c−g, 9l, m were previously reported.10 The reactions were
carried out on a 5 mmol scale; reported are total yields of two steps: DCC coupling and diazo transfer.
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The Journal of Organic Chemistry
1
1-(Phenylethynyl)cyclopentyl 2-Diazo-2-(4-methoxyphenyl)acetate (9b). 1.24 g, 69% yield. Orange oil. H
NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (comp, 2H), 7.42 (d, J = 8.9 Hz, 2H), 7.33 – 7.28 (comp, 3H), 6.95 (d, J =
9.0 Hz, 2H), 3.82 (s, 3H), 2.42 (ddd, J = 12.3, 7.8, 3.7 Hz, 2H), 2.35 – 2.26 (comp, 2H), 1.90 – 1.78 (comp, 4H).
13C NMR (126 MHz, CDCl3) δ 164.1, 158.0, 131.8, 128.3, 128.1, 125.9, 122.7, 117.1, 114.6, 89.5, 85.0, 82.0,
55.4, 40.8, 23.5. IR (neat) 2954, 2075, 1702, 1512, 1255, 1145, 997 cmꢀ1; HRMS (ESI) m/z calculated for
C22H20N2O3Na [M+Na]+ 383.1366, found: 383.1361.
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2
3
4
5
6
7
8
9
1-(Phenylethynyl)cyclopentyl 2-Diazo-2-(thiophen-2-yl)acetate (9h). 874 mg, 52% yield. Darkꢀred oil. 1H NMR
(500 MHz, CDCl3) δ 7.46 (dd, J = 6.4, 2.9 Hz, 2H), 7.34 – 7.28 (m, 4H), 7.07 – 7.03 (m, 1H), 6.84 (d, J = 3.6 Hz,
1H), 2.49 – 2.41 (m, 2H), 2.31 (dt, J = 15.3, 7.7 Hz, 2H), 1.87 – 1.81 (m, 4H). 13C NMR (126 MHz, CDCl3) δ
163.4, 131.9, 128.3, 128.1, 126.9, 125.9, 125.4, 122.6, 120.9, 89.0, 85.3, 82.9, 40.8, 23.4. IR (neat) 2928, 2076,
1701, 1443, 1285, 1231, 1127, 974, 691 cmꢀ1; HRMS (ESI) m/z calculated for C19H16N2O2SNa [M+Na]+
359.0825, found: 359.0822.
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1-(Phenylethynyl)cyclohexyl 2-Diazo-2-phenylacetate (9i). 1.14 g, 66% yield. Yellow solid, m.p. 50 – 51 °C.
1H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 8.5, 1.1 Hz, 2H), 7.50 – 7.45 (comp, 2H), 7.42 – 7.36 (comp, 2H),
7.34 – 7.28 (comp, 3H), 7.21 – 7.16 (m, 1H), 2.36 – 2.21 (comp, 2H), 2.09 (comp, 2H), 1.81 – 1.65 (comp, 4H),
13
1.62 – 1.53 (m, 1H), 1.45 (ddd, J = 13.1, 8.5, 4.8 Hz, 1H). C NMR (126 MHz, CDCl3) δ 163.1, 131.9, 128.9,
128.3, 128.1, 125.8, 125.7, 124.0, 122.7, 89.1, 86.5, 77.1, 37.5, 25.2, 22.7. IR (neat) 2936, 2083, 1707, 1241,
754, 691 cmꢀ1; HRMS (ESI) m/z calculated for C22H20N2O2Na [M+Na]+ 367.1417, found: 367.1410.
1-(Phenylethynyl)cyclododecyl 2-Diazo-2-phenylacetate (9j). 1.33 g, 62% yield. Yellow solid, m.p. 92.5 – 93.5
1
°C. H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 0.9 Hz, 2H), 7.50 – 7.44 (comp, 2H), 7.42 – 7.35 (comp,
2H), 7.34 – 7.27 (comp, 3H), 7.19 (ddd, J = 8.6, 2.2, 1.1 Hz, 1H), 2.37 – 2.23 (comp, 2H), 2.12 – 1.98 (comp,
13
2H), 1.68 (d, J = 8.8 Hz, 2H), 1.43 (comp, 16H). C NMR (126 MHz, CDCl3) δ 163.1, 131.9, 128.9, 128.3,
128.1, 125.8, 125.7, 124.0, 122.7, 89.4, 86.2, 79.6, 33.4, 26.1, 25.9, 22.3, 22.1, 19.4. IR (neat) 2928, 2079, 1705,
1470, 1241, 1146, 1006, 754 cmꢀ1; HRMS (ESI) m/z calculated for C28H32N2O2Na [M+Na]+ 451.2356, found:
451.2343.
4-(Phenylethynyl)tetrahydro-2H-pyran-4-yl 2-Diazo-2-phenylacetate (9k). 1.12 g, 65% yield. Yellow solid,
1
m.p. 85 – 86 °C. H NMR (500 MHz, CDCl3) δ 7.57 – 7.45 (comp, 4H), 7.44 – 7.36 (comp, 2H), 7.36 – 7.28
(comp, 3H), 7.23 – 7.17 (m, 1H), 3.93 (dt, J = 9.2, 4.4 Hz, 2H), 3.85 (ddd, J = 11.9, 9.0, 2.9 Hz, 2H), 2.45 – 2.38
(comp, 2H), 2.23 (ddd, J = 13.1, 9.0, 4.0 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 163.0, 131.9, 128.9, 128.7,
128.2, 125.9, 125.4, 124.1, 122.2, 87.5, 87.5, 74.1, 64.5, 38.0. IR (neat) 2960, 2086, 1707, 1498, 1241, 1140, 755
cmꢀ1; HRMS (ESI) m/z calculated for C21H18N2O3Na [M+Na]+ 369.1214, found: 369.1210.
1-((4-Methoxyphenyl)ethynyl)cyclopentyl 2-Diazo-2-(4-methoxyphenyl)acetate (9n). 1.13 g, 58% yield. Orange
oil. 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 10.1, 9.0 Hz, 4H), 6.94 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 8.9 Hz,
2H), 3.81 (s, 3H), 3.80 (s, 3H), 2.46 – 2.37 (m, 2H), 2.34 – 2.24 (m, 2H), 1.87 – 1.78 (m, 4H). 13C NMR (126
MHz, CDCl3) δ 164.1, 159.6, 158.0, 133.3, 125.9, 117.1, 114.8, 114.5, 113.8, 88.1, 84.9, 82.3, 55.34, 55.25, 40.8,
23.5. IR (neat) 2956, 2080, 1703, 1511, 1248, 1147, 830, 734 cmꢀ1; HRMS (ESI) m/z calculated for
C23H22N2O4Na [M+Na]+ 413.1472, found: 413.1483.
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1-((4-Methoxyphenyl)ethynyl)cyclopentyl 2-Diazo-2-[(4-(trifluorometh-yl)phenyl]acetate (9o). 1.18 g, 55%
1
2
1
yield. Orange oil. H NMR (500 MHz, CDCl3) δ 7.72 – 7.52 (comp, 4H), 7.40 (d, J = 8.6 Hz, 2H), 6.83 (d, J =
3
4
5
6
7
8
9
8.7 Hz, 2H), 3.81 (s, 3H), 2.50 – 2.37 (comp, 2H), 2.37 – 2.22 (comp, 2H), 1.85 (comp, 4H). 13C NMR (126
MHz, CDCl3) δ 162.8, 159.7, 133.3, 130.3, 127.5 (q, J = 32.5 Hz), 125.7 (q, J = 3.8 Hz), 123.5, 114.6, 113.8,
87.6, 85.3, 82.9, 77.3, 77.0, 76.8, 55.3, 40.8, 23.4. IR (neat) 2957, 2087, 1706, 1509, 1323, 1244, 1070, 832 cmꢀ1;
HRMS (ESI) m/z calculated for C23H19F3N2O3Na [M+Na]+ 451.1240, found: 451.1225.
1
2-Methyl-4-phenylbut-3-yn-2-yl 2-Diazo-2-phenylacetate (9p). 958 mg, 63% yield. Orange oil. H NMR (300
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MHz, CDCl3) δ 7.53 – 7.43 (comp, 4H), 7.41 – 7.35 (comp, 2H), 7.32 – 7.27 (comp, 3H), 7.21 – 7.14 (m, 1H),
1.85 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 163.4, 131.9, 128.9, 128.4, 128.2, 125.7, 125.7, 124.0, 122.5, 90.0,
84.5, 73.8, 29.4. IR (neat) 2936, 2079, 1705, 1498, 1349, 1247, 1120, 754, 691 cmꢀ1; HRMS (ESI) m/z calculated
for C19H16N2O2Na [M+Na]+ 327.1104, found: 327.1102.
2-Methyl-4-phenylbut-3-yn-2-yl 2-Diazo-2-(4-methoxyphenyl)acetate (7 or 9q). 1.14 g, 68% yield. Orange oil.
1H NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (comp, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.34 – 7.28 (comp, 3H), 6.95 (d,
J = 9.0 Hz, 2H), 3.82 (s, 3H), 1.85 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 163.9, 158.0, 131.9, 128.4, 128.1,
126.0, 122.6, 117.2, 114.6, 90.1, 84.4, 73.7, 55.4, 29.5. IR (neat) 2988, 2079, 1705, 1514, 1258, 1122, 998, 827
cmꢀ1; HRMS (ESI) m/z calculated for C20H18N2O3Na [M+Na]+ 357.1210, found: 357.1209.
1-(Phenylethynyl)cyclobutyl 2-Diazo-2-phenylacetate (9r). 822 mg, 52% yield. Yellow solid, m.p. 76 – 77 °C.
1H NMR (500 MHz, CDCl3) δ 7.52 (dd, J = 8.5, 1.1 Hz, 2H), 7.50 – 7.45 (comp, 2H), 7.42 – 7.36 (comp, 2H),
7.34 – 7.29 (comp, 3H), 7.23 – 7.16 (m, 1H), 2.81 – 2.71 (comp, 2H), 2.62 (ddd, J = 12.7, 9.8, 2.6 Hz, 2H), 2.15
13
– 2.05 (m, 1H), 2.00 (ddd, J = 9.8, 8.6, 4.9 Hz, 1H). C NMR (126 MHz, CDCl3) δ 163.2, 131.9, 128.9, 128.4,
128.2, 125.8, 125.5, 124.0, 122.5, 89.2, 84.8, 73.3, 37.2, 14.7. IR (neat) 2952, 2081, 1704, 1497, 1351, 1242,
1144, 1088, 754, 691 cmꢀ1; HRMS (ESI) m/z calculated for C20H16N2O2Na [M+Na]+ 339.1104, found: 339.1107.
2-Methyl-4-phenylbut-3-yn-2-yl 2-Diazo-3-oxobutanoate (14). Prepared according to general procedure1 from
acetoacetic acid; 797 mg, 59% yield. Pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.49 – 7.40 (comp, 2H), 7.35
13
– 7.27 (comp, 3H), 2.49 (s, 3H), 1.83 (s, 6H). C NMR (126 MHz, CDCl3) δ 190.3, 159.6, 131.8, 128.6, 128.2,
122.2, 89.2, 85.0, 74.7, 29.4, 28.3. IR (neat) 2988, 2137, 1719, 1655, 1315, 1121, 1058, 693 cmꢀ1; HRMS (ESI)
m/z calculated for C15H14N2O3Na [M+Na]+ 293.0897, found: 293.0891.
2-Methyl-4-phenylbut-3-yn-2-yl 2-Diazoacetate (15). Prepared according to literature procedure7e for the
1
related diazo compounds; 524 mg, 46% total yield. Yellow oil. H NMR (500 MHz, CDCl3) δ 7.45 (dt, J = 8.2,
3.7 Hz, 2H), 7.30 (dd, J = 4.7, 2.3 Hz, 3H), 4.72 (s, 1H), 1.80 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 131.8,
128.4, 128.1, 122.5, 90.1, 84.2, 73.5, 46.7, 29.4. IR (neat) 2987, 2111, 1701, 1370, 1186, 1124, 983, 693 cmꢀ1;
HRMS (ESI) m/z calculated for C13H12N2O2Na [M+Na]+ 251.0791, found: 251.0798.
2-Methyl-4-phenylbut-3-yn-2-yl
3-(tert-Butyldimethylsilyl)oxy-2-diazo-but-3-enoate
(16).
Synthesized
1
according to the published procedure19 from compound 14; 1.67 g, 88% yield. Yellow oil. H NMR (500 MHz,
CDCl3) δ 7.48 – 7.43 (comp, 2H), 7.34 – 7.28 (comp, 3H), 5.03 (d, J = 2.1 Hz, 1H), 4.26 (d, J = 2.1 Hz, 1H), 1.81
13
(s, 6H), 0.93 (s, 9H), 0.24 (s, 6H). C NMR (126 MHz, CDCl3) δ 162.5, 140.9, 131.8, 128.4, 128.1, 122.5, 90.4,
89.9, 84.4, 73.6, 29.4, 25.6, 18.1, −4.8. IR (neat) 2956, 2088, 1715, 1342, 1255, 1057, 842 cmꢀ1; HRMS (ESI) m/z
calculated for C21H28N2O3SiNa [M+Na]+ 407.1761, found: 407.1745.
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The Journal of Organic Chemistry
General Procedure for Gold(I)ꢀCatalyzed Domino Cascade Transformation of Phenylpropargyl
Phenyldiazoacetates. To a flameꢀdried 10 mL Schlenk flask charged with a magnetic stirring bar cationic
gold(I) catalyst (0.010 mmol) and 2.0 mL DCM were added under nitrogen atmosphere. 1ꢀ
(Phenylethynyl)cyclopentyl 2ꢀdiazoꢀ2ꢀphenylacetate 1 (0.20 mmol) dissolved in 2.0 mL of DCM was added in
one portion into the solution under the flow of nitrogen. The resulting mixture was stirred for 12 h at room
temperature (20 °C); the reaction mixture was purified by column chromatography (100:1 to 10:1 gradient of
hexanes: ethyl acetate as eluents) to afford pure 8'-Phenylspiro[cyclopentane-1,1'-indeno[1,2-c]furan]-3'(8'H)-
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one (2) as a white solid (52 mg, 86% using catalyst [Au(JohnPhos)(MeCN)]SbF6); m.p. 128 – 129 °C. H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.33 – 7.30 (comp, 3H), 7.27 – 7.24 (comp,
2H), 7.08 – 7.06 (comp, 2H), 4.80 (s, 1H), 2.11 – 2.08 (comp, 2H), 2.07 – 2.02, (m, 1H), 2.01 – 1.98 (m, 1H),
1.98 – 1.82 (m, 1H), 1.81 – 1.69 (m, 1H), 1.67 – 1.55 (m, 1H), 1.33 – 1.25 (m, 1H); 13C NMR (400 MHz, CDCl3)
δ 179.0, 166.4, 152.0, 136.1, 135.9, 134.3, 129.1, 128.1, 127.9, 127.7, 125.0, 120.9, 95.5, 52.4, 38.5, 36.7, 24.4.
IR (neat) 2961, 1751, 1453, 1090, 953, 771 cmꢀ1; HRMS (ESI) m/z calculated for C21H18O2Na [M+Na]+
325.1199, found: 325.1200.
8'-Phenylspiro[cyclobutane-1,1'-indeno[1,2-c]furan]-3'(8'H)-one (13). Obtained using
5
mol
%
of
Au(C4H8S)Cl at 80 °C in DCE for 12 h: 40.3 mg, 70% yield. White solid, m.p. 150–151 °C. 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J= 8.2 Hz, 1H), 7.38 – 7.32 (comp, 4H), 7.27 – 7.21 (comp, 2H), 7.15 – 7.13 (comp, 2H), 4.89
(s, 1H), 2.82 – 2.74 (m, 1H), 2.51 – 2.47 (comp, 2H), 1.84 – 1.73 (comp, 2H), 1.60 – 1.50 (m, 1H); 13C NMR
(400 MHz, CDCl3) δ 178.2, 166.2, 152.2, 135.8, 135.5, 133.8, 129.0, 128.1, 127.9, 127.0, 125.0, 120.9, 85.9,
52.4, 33.3, 31.7, 12.2. IR (neat) 1756, 1454, 1154, 1066, 991, 722, 700 cmꢀ1; HRMS (ESI) m/z calculated for
C20H16O2Na [M+Na]+ 311.1043, found: 311.1050.
General Procedure for the Synthesis of 1,5ꢀDihydroꢀ4Hꢀpyrazolꢀ4ꢀones 10 and 11. To a flameꢀdried 10 mL
Schlenk flask charged with a magnetic stirring bar, AuCl(C4H8S) catalyst (0.010 mmol) and 2.0 mL DCE were
added under nitrogen atmosphere. Propargyl aryldiazoacetate 1 or 9 (0.20 mmol) dissolved in 2.0 mL of DCE
was added in one portion into the solution under the flow of nitrogen. The resulting mixture was stirred for 72 h
at room temperature (20 °C). Solvent was evaporated, and products were purified by column chromatography
(100:1 to 10:1 gradient of hexanes: ethyl acetate as eluents) to afford pure compounds 10 and 11.
5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-phenyl-1,5-dihydro-4H-pyrazol-4-one (3 or10a). 37.6 mg, 57% yield.
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Yellow solid, m.p. 115–116 °C. H NMR (500 MHz, CDCl3) δ 8.18 (dd, J = 7.9, 1.2 Hz, 2H), 8.08 (dd, J = 7.9,
1.2 Hz, 2H), 7.90 (br, 1H), 7.62 – 7.57 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 – 7.36 (comp, 3H), 5.88 – 5.84 (m,
1H), 2.50 – 2.41 (comp, 3H), 2.35 – 2.29 (m, 1H), 1.98 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.1,
189.7, 143.8, 138.5, 134.0, 133.4, 131.6, 130.7, 129.2, 129.1, 128.5, 128.4, 126.0, 81.5, 32.4, 32.4, 23.0. IR
(neat) 3358, 1721, 1674, 1246, 903 cmꢀ1; HRMS (ESI) m/z calculated for C21H18N2O2Na [M+Na]+ 353.1260,
found: 353.1247.
5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (4 or 11a). 12.5 mg, 19% yield.
Yellow solid, m.p. 130–131 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 7.5 Hz, 2H), 7.66 (br, 1H), 7.50 (t, J =
7.5 Hz, 1H), 7.42 – 7.33 (comp, 7H), 6.84 – 6.80 (m, 1H), 2.75 – 2.70 (comp, 2H), 2.56 – 2.49 (comp, 2H), 1.96
– 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.7, 189.5, 143.2, 135.7, 134.1, 133.7, 133.1, 132.0, 130.9,
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129.5, 128.8, 128.5, 126.5, 81.8, 34.1, 32.7, 22.2. IR (neat) 3343, 1732, 1675, 1447, 1231, 738 cmꢀ1; HRMS
(ESI) m/z calculated for C21H18N2O2Na [M+Na]+ 353.1260, found: 353.1249.
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5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-(4-methoxyphenyl)-1,5-dihydro-4H-pyrazol-4-one (10b). 36.3 mg, 54%
1
yield. Yellow solid, m.p. 44–46 °C. H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 7.3 Hz, 2H), 8.03 (d, J = 9.0 Hz,
2H), 7.73 (s, 1H), 7.62 – 7.56 (m, 1H), 7.50 – 7.44 (comp, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.87 – 5.82 (m, 1H),
3.84 (s, 3H), 2.52 – 2.39 (comp, 3H), 2.31 (dddd, J = 17.5, 9.3, 5.8, 2.1 Hz, 1H), 2.02 – 1.84 (comp, 2H). 13C
NMR (126 MHz, CDCl3) δ 192.5, 189.9, 160.5, 144.2, 138.7, 133.9, 133.5, 131.4, 130.7, 128.3, 127.6, 121.7,
114.0, 81.3, 55.3, 32.5, 32.4, 23.0. IR (neat) 3338, 2931, 1712, 1674, 1608, 1510, 1251, 1176, 835 cmꢀ1; HRMS
(EI) m/z calculated for C22H19N2O3 [M−H]− 359.1401, found: 359.1396.
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5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-(4-methoxyphenyl)-1,5-dihydro-4H-pyrazol-4-one (11b). 14.1 mg, 21%
yield. Yellow solid, m.p. 60.5–61.5 °C. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.73 (s, 1H), 7.53
– 7.47 (m, 1H), 7.36 (dd, J = 11.7, 4.0 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 6.82 – 6.81 (m,
1H), 3.80 (s, 3H), 2.76 – 2.68 (m, 2H), 2.52 (d, J = 5.6 Hz, 2H), 1.96 – 1.88 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 193.1, 189.7, 159.8, 143.2, 133.9, 133.6, 133.1, 132.1, 131.0, 128.4, 127.9, 127.8, 114.9, 81.6, 55.3,
34.1, 32.7, 22.2. IR (neat) 3344, 2954, 1736, 1673, 1608, 1510, 1252, 692 cmꢀ1; HRMS (EI) m/z calculated for
C22H19N2O3 [M−H]− 359.1401, found: 359.1406.
5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-(p-tolyl)-1,5-dihydro-4H-pyrazol-4-one (10c). 42.0 mg, 61% yield. Yellow
oil. 1H NMR (500 MHz, CDCl3) δ 8.19 – 8.14 (comp, 2H), 7.97 – 7.92 (comp, 2H), 7.78 (s, 1H), 7.60 – 7.56 (m,
1H), 7.47 – 7.43 (comp, 2H), 7.21 – 7.18 (comp, 2H), 5.85 – 5.82 (m, 1H), 2.46 – 2.38 (comp, 3H), 2.36 (s, 3H),
2.31 – 2.26 (m, 1H), 1.96 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.3, 189.8, 144.2, 139.3, 138.6,
134.0, 133.5, 131.5, 130.7, 129.2, 128.4, 128.3, 126.0, 81.4, 32.5, 32.4, 23.0, 21.4. IR (neat) 3344, 1722, 1676,
1231, 951 cmꢀ1; HRMS (ESI) m/z calculated for C22H20N2O2Na [M+Na]+ 367.1417, found: 367.1404.
5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-(p-tolyl)-1,5-dihydro-4H-pyrazol-4-one (11c). 16.5 mg, 24% yield. Yellow
oil. 1H NMR (500 MHz, CDCl3) δ 7.88 – 7.80 (comp, 2H), 7.67 (s, 1H), 7.51 – 7.47 (m, 1H), 7.37 – 7.32 (comp,
2H), 7.24 – 7.16 (comp, 4H), 6.83 – 6.78 (m, 1H), 2.74 – 2.68 (comp, 2H), 2.55 – 2.48 (comp, 2H), 2.34 (s, 3H),
1.96 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.9, 189.6, 143.2, 138.8, 133.9, 133.7, 133.1, 132.9,
132.0, 131.0, 130.2, 128.4, 126.4, 81.8, 34.1, 32.7, 22.2, 21.1. IR (neat) 3348, 1737, 1675, 1230, 809 cmꢀ1;
HRMS (ESI) m/z calculated for C22H20N2O2Na [M+Na]+ 367.1417, found: 367.1407.
3-([1,1'-Biphenyl]-4-yl)-5-benzoyl-5-(cyclopent-1-en-1-yl)-1,5-dihydro-4H-pyrazol-4-one (10d). 56.0 mg, 69%
1
yield. Yellow solid, m.p. 49–51 °C. H NMR (500 MHz, CDCl3) δ 8.23 – 8.15 (comp, 2H), 7.98 (s, 1H), 7.68 –
7.58 (comp, 6H), 7.47 (dt, J = 12.5, 7.9 Hz, 5H), 7.37 (t, J = 7.4 Hz, 1H), 5.89 (m, 1H), 2.59 – 2.40 (comp, 3H),
2.35 (ddd, J = 15.2, 11.0, 4.0 Hz, 1H), 2.04 – 1.86 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.1, 189.8,
143.5, 141.8, 140.5, 138.5, 134.0, 133.5, 131.7, 130.7, 128.8, 128.4, 128.1, 127.6, 127.2, 127.0, 126.4, 81.6, 32.5,
23.0. IR (neat) 3346, 2957, 1725, 1674, 1233, 907, 733 cmꢀ1; HRMS (EI) m/z calculated for C27H21N2O2 [M−H]−
405.1609, found: 405.1610.
5-([1,1'-Biphenyl]-4-yl)-5-benzoyl-3-(cyclopent-1-en-1-yl)-1,5-dihydro-4H-pyrazol-4-one (11d). 7.3 mg, 9%
1
yield. Yellow solid, m.p. 80–81 °C. H NMR (500 MHz, CDCl3) δ 7.92 – 7.88 (comp, 2H), 7.78 (s, 1H), 7.67 –
7.61 (comp, 3H), 7.60 – 7.55 (comp, 2H), 7.52 (dd, J = 11.1, 3.7 Hz, 1H), 7.48 – 7.42 (comp, 3H), 7.38 (dd, J =
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15.9, 7.7 Hz, 3H), 6.88 – 6.83 (m, 1H), 2.79 – 2.72 (comp, 2H), 2.58 – 2.51 (comp, 2H), 1.98 – 1.90 (comp, 2H).
13C NMR (126 MHz, CDCl3) δ 192.8, 189.5, 143.2, 141.7, 140.0, 134.6, 134.2, 133.8, 133.1, 132.0, 131.0, 128.9,
128.6, 128.2, 127.7, 127.1, 126.9, 81.6, 34.1, 32.7, 22.2. IR (neat) 3342, 2953, 1728, 1674, 1487, 1229, 1008,
735, 696 cmꢀ1; HRMS (EI) m/z calculated for C27H21N2O2 [M−H]− 405.1609, found: 405.1604.
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5-Benzoyl-3-(4-bromophenyl)-5-(cyclopent-1-en-1-yl)-1,5-dihydro-4H-pyrazol-4-one (10e). 60.4 mg, 74%
yield. Yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.19 – 8.14 (comp, 2H), 7.97 – 7.92 (comp, 3H), 7.61 – 7.57 (m,
1H), 7.52 – 7.49 (comp, 2H), 7.47 – 7.43 (comp, 2H), 5.86 – 5.83 (m, 1H), 2.47 – 2.39 (comp, 3H), 2.32 – 2.26
(m, 1H), 1.96 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.7, 189.5, 142.7, 138.3, 134.1, 133.3, 131.8,
131.7, 130.8, 128.4, 128.1, 127.4, 123.4, 81.7, 32.5, 32.4, 22.9. IR (neat) 3336, 1724, 1673, 1231, 1009 cmꢀ1;
HRMS (ESI) m/z calculated for C21H17N2O2NaBr [M+Na]+ 431.0366, found: 431.0350.
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5-Benzoyl-5-(4-bromophenyl)-3-(cyclopent-1-en-1-yl)-1,5-dihydro-4H-pyrazol-4-one (11e). 10.6 mg, 13%
1
yield. Yellow oil. H NMR (500 MHz, CDCl3) δ 7.83 – 7.79 (comp, 2H), 7.62 (s, 1H), 7.54 – 7.50 (comp, 3H),
7.39 – 7.35 (comp, 2H), 7.26 – 7.23 (comp, 2H), 6.83 – 6.80 (m, 1H), 2.74 – 2.68 (comp, 2H), 2.54 – 2.50 (comp,
2H), 1.95 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.4, 189.1, 143.3, 134.7, 134.6, 133.9, 132.9,
132.6, 131.9, 130.8, 128.7, 128.2, 123.2, 81.0, 77.3, 77.0, 76.8, 34.1, 32.7, 22.2. IR (neat) 3338, 1719, 1674,
1230, 908 cmꢀ1; HRMS (ESI) m/z calculated for C21H17N2O2NaBr [M+Na]+ 431.0366, found: 431.0345.
5-Benzoyl-3-(4-chlorophenyl)-5-(cyclopent-1-en-1-yl)-1,5-dihydro-4H-pyrazol-4-one (10f). 50.2 mg, 69%
yield. Yellow solid, m.p. 77.5–78.5 °C. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5
Hz, 2H), 7.91 (s, 1H), 7.62 – 7.57 (m, 1H), 7.49 – 7.45 (comp, 2H), 7.38 – 7.34 (comp, 2H), 5.87 – 5.83 (m, 1H),
2.49 – 2.39 (comp, 3H), 2.33 – 2.26 (m, 1H), 1.97 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.8,
189.5, 142.7, 138.3, 135.0, 134.1, 133.3, 131.8, 130.7, 128.7, 128.4, 127.6, 127.2, 81.7, 32.5, 32.4, 22.9. IR
(neat) 3345, 1716, 1673, 1231, 1116 cmꢀ1; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na]+ 387.0871,
found: 387.0857.
5-Benzoyl-5-(4-chlorophenyl)-3-(cyclopent-1-en-1-yl)-1,5-dihydro-4H-pyrazol-4-one (11f). 10.2 mg, 14%
yield. Yellow solid, m.p. 94–95 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 – 7.80 (comp, 2H), 7.67 (s, 1H), 7.55 –
7.51 (m, 1H), 7.40 – 7.36 (comp, 4H), 7.34 – 7.30 (comp, 2H), 6.85 – 6.81 (m, 1H), 2.75 – 2.69 (comp, 2H), 2.56
– 2.51 (copm, 2H), 1.96 – 1.90 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.5, 189.1, 143.3, 135.0, 134.5,
134.1, 133.9, 132.9, 131.9, 130.8, 129.7, 128.6, 127.9, 80.9, 34.1, 32.7, 22.2. IR (neat) 3344, 1717, 1671, 1228,
933 cmꢀ1; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na]+ 387.0871, found: 387.0858.
5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-[4-(trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one (10g). 40.6
mg, 51% yield. Yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.22 – 8.16 (comp, 4H), 8.07 (br, 1H), 7.63 (d, J = 8.5
Hz, 2H), 7.60 – 7.56 (m, 1H), 7.50 – 7.47 (comp, 2H), 5.88 – 5.86 (m, 1H), 2.47 – 2.40 (comp, 3H), 2.33 – 2.27
(m, 1H), 1.98 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.4, 189.3, 141.9, 138.1, 134.2, 133.6, 133.3,
132.8, 132.6, 131.9(q, J = 30.0 Hz), 129.3, 128.4, 127.9, 125.4 (q, J = 3.8 Hz) 124.5 (q, J = 278.8 Hz), 81.9, 32.4,
32.4, 23.0. IR (neat) 3334, 1709, 1673, 1321, 1120 cmꢀ1; HRMS (ESI) m/z calculated for C22H17N2O2F3Na
[M+Na]+ 421.1134, found: 421.1116.
5-Benzoyl-3-(cyclopent-1-en-1-yl)-5-[4-(trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one (11g). 17.5
mg, 22% yield. Yellow solid, m.p. 45.5–46.5 °C. 1H NMR (500 MHz, CDCl3) δ 7.82 – 7.76 (comp, 2H), 7.68 –
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7.63 (comp, 3H), 7.55 – 7.50 (comp, 3H), 7.38 (t, J = 7.8 Hz, 2H), 6.85 – 6.83 (m, 1H), 2.75 – 2.69 (comp, 2H),
2.56 – 2.51 (comp, 2H), 1.97 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.1, 188.9, 143.3, 139.3,
134.8, 134.1, 132.9, 131.8, 131.0 (q, J = 32.5 Hz) 130.6 128.8, 126.9, 126.4 (q, J = 3.8 Hz), 121.5 (q, J = 270 Hz)
80.8, 34.1, 32.7, 22.2. IR (neat) 3335, 1729, 1675, 1119, 907 cmꢀ1; HRMS (ESI) m/z calculated for
C22H17N2O2F3Na [M+Na]+ 421.1134, found: 421.1119.
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5-Benzoyl-5-(cyclopent-1-en-1-yl)-3-(thiophen-2-yl)-1,5-dihydro-4H-pyrazol-4-one (10h). 39.7 mg, 59%
yield.20 Yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 7.3 Hz, 2H), 7.82 (s, 1H), 7.80 (dd, J = 3.7, 0.8 Hz,
1H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 5.1 Hz, 1H), 7.08 (dd, J = 4.9, 3.8 Hz, 1H),
5.88 – 5.84 (m, 1H), 2.48 – 2.37 (comp, 3H), 2.37 – 2.26 (m, 1H), 1.91 (comp, 2H). 13C NMR (126 MHz, CDCl3)
δ 190.7, 189.5, 141.6, 138.3, 134.1, 130.7, 128.4, 127.7, 126.7, 81.2, 32.4, 23.0. IR (neat) 3337, 2926, 1722,
1674, 1228, 731, 692 cmꢀ1; HRMS (ESI) m/z calculated for C19H16N2O2SNa [M+Na]+ 359.0825, found:
359.0823.
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5-Benzoyl-5-(cyclohex-1-en-1-yl)-3-phenyl-1,5-dihydro-4H-pyrazol-4-one (10i). 39.2 mg, 57% yield. Yellow
oil. 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, J = 5.3, 3.3 Hz, 2H), 8.13 – 7.95 (m, 2H), 7.84 (s, 1H), 7.59 (ddd, J =
6.7, 4.0, 1.3 Hz, 1H), 7.52 – 7.43 (comp, 2H), 7.42 – 7.32 (comp, 3H), 5.84 (t, J = 2.7 Hz, 1H), 2.11 (comp, 2H),
1.63 (comp, 6H). 13C NMR (126 MHz, CDCl3) δ 192.3, 190.4, 143.7, 134.1, 133.9, 133.5, 130.8, 129.2, 129.1,
128.5, 128.5, 128.3, 128.2, 127.7, 126.0, 84.9, 25.9, 25.5, 22.6, 21.6. IR (neat) 3343, 2927, 1729, 1674, 1447,
1231, 695 cmꢀ1; HRMS (EI) m/z calculated for C22H19N2O2 [M−H]− 343.1452, found: 343.1449.
5-Benzoyl-3-(cyclohex-1-en-1-yl)-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (11i). 11.0 mg, 16% yield. Yellow
solid, m.p. 63–64 °C. 1H NMR (300 MHz, CDCl3) δ 7.83 (dd, J = 8.4, 1.2 Hz, 2H), 7.56 (br, 1H), 7.49 (dd, J =
10.5, 4.4 Hz, 1H), 7.41 – 7.31 (comp, 7H), 7.02 (m, 1H), 2.40 (comp, 2H), 2.18 (comp, 2H), 1.76 – 1.55 (comp,
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4H). C NMR (126 MHz, CDCl3) δ 193.1, 189.6, 145.0, 135.9, 133.7, 133.1, 131.5, 131.0, 129.5, 128.7, 128.5,
127.7, 126.5, 82.1, 25.7, 25.2, 22.3, 21.9. IR (neat) 3339, 2927, 1732, 1675, 1447, 1231, 698 cmꢀ1; HRMS (EI)
m/z calculated for C22H19N2O2 [M−H]− 343.1452, found: 343.1448.
5-Benzoyl-5-(cyclododec-1-en-1-yl)-3-phenyl-1,5-dihydro-4H-pyrazol-4-one (10j). 43.7 mg, 51% yield. Yellow
solid, m.p. 69–70 °C. 1H NMR (500 MHz, CDCl3) δ 8.15 – 8.05 (comp, 2H), 7.89 (s, 1H), 7.64 – 7.31 (comp,
8H), 5.48 – 5.42 (m, 1H), 2.69 – 2.44 (comp, 2H), 2.32 – 2.18 (m, 1H), 2.09 – 1.96 (m, 1H), 1.55 – 1.19 (comp,
16H). 13C NMR (126 MHz, CDCl3) δ 192.2, 190.3, 143.5, 143.5, 135.7, 135.0, 133.7, 131.6, 131.4, 129.0, 128.5,
128.2, 127.8, 127.1, 125.9, 85.7, 26.4, 25.53, 25.48, 25.09, 25.05, 24.74, 24.72, 24.1, 22.6, 22.4. IR (neat) 3351,
2928, 1699, 1677, 1448, 1344, 693 cmꢀ1; HRMS (ESI) m/z calculated for C28H32N2O2Na [M+Na]+ 451.2356,
found: 451.2347.
5-Benzoyl-3-(cyclododec-1-en-1-yl)-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (11j). 30.0 mg, 35% yield. Yellow
solid, m.p. 71–72 °C. 1H NMR (500 MHz, CDCl3) δ 7.85 (dt, J = 8.5, 1.5 Hz, 2H), 7.66 (s, 1H), 7.52 – 7.47 (m,
1H), 7.44 – 7.31 (comp, 7H), 6.79 (t, J = 8.1 Hz, 1H), 2.57 (t, J = 6.8 Hz, 2H), 2.30 – 2.17 (comp, 2H), 1.67 –
1.59 (comp, 2H), 1.54 (dt, J = 9.6, 7.2 Hz, 2H), 1.49 – 1.41 (comp, 4H), 1.40 – 1.31 (comp, 6H), 1.30 – 1.23
(comp, 2H). 13C NMR (126 MHz, CDCl3) δ 193.4, 189.6, 145.0, 136.0, 135.4, 133.6, 133.2, 130.9, 129.9, 129.5,
128.7, 128.5, 126.5, 81.9, 26.6, 26.1, 25.6, 25.2, 25.1, 24.9, 24.6, 23.7, 22.9, 22.2. IR (neat) 3347, 2924, 2850,
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1729, 1672, 1447, 1229, 737, 696 cmꢀ1; HRMS (ESI) m/z calculated for C28H32N2O2Na [M+Na]+ 451.2356,
found: 451.2349.
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5-Benzoyl-5-(3,6-dihydro-2H-pyran-4-yl)-3-phenyl-1,5-dihydro-4H-pyrazol-4-one (10k). 24.9 mg, 36% yield.
Yellow solid, m.p. 67–68 °C. 1H NMR (500 MHz, CDCl3) δ 8.23 – 8.12 (comp, 2H), 8.10 – 8.03 (m, 1H), 7.84
(dd, J = 6.3, 3.1 Hz, 1H), 7.56 – 7.30 (comp, 5H), 7.27 (comp, 2H), 5.91 – 5.88 (m, 1H), 4.22 (dd, J = 5.3, 2.6
Hz, 2H), 3.89 (ddt, J = 16.8, 11.9, 6.2 Hz, 1H), 3.78 – 3.64 (m, 1H), 2.70 – 2.41 (m, 1H), 2.37 – 2.05 (m, 1H).
13C NMR (126 MHz, CDCl3) δ 191.8, 189.6, 144.1, 134.2, 131.7, 131.6, 131.0, 130.7, 129.4, 128.6, 128.5, 126.7,
126.0, 83.5, 65.3, 64.0, 25.8. IR (neat) 3332, 2925, 2085, 1710, 1677, 1447, 1232, 700 cmꢀ1; HRMS (EI) m/z
calculated for C21H17N2O3 [M−H]− 345.1245, found: 345.1243.
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5-Benzoyl-3-(3,6-dihydro-2H-pyran-4-yl)-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (11k). 6.9 mg, 10% yield.
Yellow solid, m.p. 70–71 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.52 (td, J =
7.6, 1.0 Hz, 1H), 7.44 – 7.33 (comp, 7H), 6.99 (m, 1H), 4.29 (comp, 2H), 3.89 (dd, J = 10.5, 5.2 Hz, 2H), 2.54
(comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.6, 189.3, 143.2, 135.6, 133.8, 133.0, 130.9, 129.6, 128.9, 128.5,
128.5, 126.4, 125.1, 82.4, 65.4, 64.1, 25.1. IR (neat) 3322, 2923, 2085, 1708, 1675, 1447, 1232, 1131, 694 cmꢀ1;
HRMS (EI) m/z calculated for C21H17N2O3 [M−H]− 345.1245, found: 345.1239.
5-(4-Chlorobenzoyl)-5-(cyclopent-1-en-1-yl)-3-phenyl-1,5-dihydro-4H-pyrazol-4-one (10l). 45.1 mg, 62%
yield. Yellow solid, m.p. 85–86 °C. 1H NMR (500 MHz, CDCl3) δ 8.21 – 8.15 (comp, 2H), 8.08 – 8.03 (comp,
2H), 7.92 (s, 1H), 7.46 – 7.43 (comp, 2H), 7.41 – 7.37 (comp, 3H), 5.85 – 5.82 (m, 1H), 2.47 – 2.40 (comp, 3H),
2.29 – 2.24 (m, 1H), 1.97 – 1.88 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.0, 188.7, 143.9, 140.7, 138.4,
132.4, 132.1, 131.5, 129.3, 129.0, 128.7, 128.5, 126.0, 81.6, 77.3, 77.0, 76.8, 32.5, 32.4, 22.9. IR (neat) 3347,
1724, 1674, 1114, 1010 cmꢀ1; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na]+ 387.0871, found:
387.0855.
5-(4-Chlorobenzoyl)-3-(cyclopent-1-en-1-yl)-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (11l). 13.1 mg, 18%
yield. Yellow solid, m.p. 92–93 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 – 7.80 (comp, 2H), 7.77 (s, 1H), 7.40 –
7.36 (comp, 3H), 7.33 – 7.30 (comp, 2H), 7.28 – 7.26 (comp, 2H), 6.82 – 6.79 (m, 1H), 2.75 – 2.71 (comp, 2H),
2.55 – 2.51 (comp, 2H), 1.95 – 1.89 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 192.7, 188.4, 143.3, 140.5,
135.7, 134.1, 132.7, 132.0, 131.0, 129.6, 129.0, 128.8, 126.7, 82.2, 77.3, 77.0, 76.8, 34.1, 32.7, 22.2. IR (neat)
3342, 1741, 1676, 1091, 907 cmꢀ1; HRMS (ESI) m/z calculated for C21H17N2O2NaCl [M+Na]+ 387.0871, found:
387.0856.
5-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-3-phenyl-1,5-dihydro-4H-pyrazol-4-one (10m). 34.6 mg, 48%
yield. Yellow solid, m.p. 53–54 °C. 1H NMR (500 MHz, CDCl3) δ 8.29 – 8.18 (comp, 2H), 8.11 – 8.02 (comp,
2H), 7.98 (s, 1H), 7.43 – 7.33 (comp, 3H), 6.98 – 6.90 (comp, 2H), 5.88 – 5.79 (m, 1H), 3.89 (s, 3H), 2.52 – 2.37
(comp, 3H), 2.32 – 2.24 (m, 1H), 2.00 – 1.84 (comp, 2H). 13C NMR (126 MHz, cdcl3) δ 192.6, 187.8, 164.2,
144.0, 139.0, 133.6, 131.4, 129.2, 129.1, 128.5, 126.1, 126.0, 113.6, 81.6, 55.5, 32.6, 32.4, 23.0. IR (neat) 3336,
2932, 2842, 1714, 1663, 1596, 1244, 1171, 1028, 842, 732 cmꢀ1; HRMS (EI) m/z calculated for C22H19N2O3
[M−H]− 359.1401, found: 359.1397.
3-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (11m). 20.9 mg, 29%
yield. Yellow solid, m.p. 72–73 °C. 1H NMR (500 MHz, CDCl3) δ 7.94 – 7.84 (comp, 2H), 7.78 (s, 1H), 7.41 –
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7.34 (comp, 3H), 7.33 – 7.29 (comp, 2H), 6.86 – 6.77 (comp, 3H), 3.81 (s, 3H), 2.77 – 2.69 (comp, 2H), 2.53
(ddd, J = 9.6, 4.8, 2.2 Hz, 2H), 1.93 (dt, J = 15.0, 7.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 193.4, 187.8,
163.9, 143.4, 136.4, 133.9, 133.8, 132.1, 129.4, 128.9, 128.7, 126.7, 125.5, 113.7, 82.2, 55.5, 34.1, 32.7, 22.2. IR
(neat) 3310, 2933, 2841, 1736, 1667, 1599, 1510, 1247, 1172, 733 cmꢀ1; HRMS (EI) m/z calculated for
C22H19N2O3 [M−H]− 359.1401, found: 359.1394.
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5-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-3-(4-methoxyphenyl)-1,5-dihydro-4H-pyrazol-4-one (10n). 42.9
mg, 55% yield. Yellow solid, m.p. 52–53 °C. 1H NMR (500 MHz, CDCl3) δ 8.29 – 8.17 (comp, 2H), 8.07 – 7.98
(comp, 2H), 7.90 (s, 1H), 6.97 – 6.87 (comp, 4H), 5.86 – 5.78 (m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.51 – 2.36
(comp, 3H), 2.28 (dddd, J = 15.3, 9.3, 5.8, 2.1 Hz, 1H), 1.99 – 1.84 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ
193.0, 187.9, 164.2, 160.4, 144.2, 139.2, 133.5, 131.1, 127.6, 126.2, 121.8, 113.9, 113.6, 81.3, 55.5, 55.3, 32.5,
32.4, 23.0. IR (neat) 3340, 2956, 2840, 1717, 1665, 1598, 1508, 1248, 1172, 1029, 837 cmꢀ1; HRMS (EI) m/z
calculated for C23H21N2O4 [M−H]− 389.1507, found: 389.1501.
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3-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-5-(4-methoxyphenyl)-1,5-dihydro-4H-pyrazol-4-one (11n). 18.7
mg, 24% yield. Yellow solid, m.p. 67–68 °C. 1H NMR (500 MHz, CDCl3) δ 7.94 – 7.86 (comp, 2H), 7.83 (s, 1H),
7.24 – 7.17 (comp, 2H), 6.92 – 6.85 (comp, 2H), 6.86 – 6.77 (comp, 3H), 3.81 (s, 3H), 3.80 – 3.77 (s, 3H), 2.77 –
2.67 (comp, 2H), 2.56 – 2.46 (comp, 2H), 1.96 – 1.87 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 193.7, 188.0,
163.8, 159.7, 143.3, 133.9, 133.6, 132.2, 128.5, 128.1, 125.6, 114.8, 113.6, 82.0, 55.5, 55.3, 34.1, 32.7, 22.2. IR
(neat) 3337, 2933, 2839, 1721, 1663, 1596, 1508, 1241, 1169, 1027, 839, 734 cmꢀ1; HRMS (EI) m/z calculated
for C23H21N2O4 [M−H]− 389.1507, found: 389.1497.
5-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-3-[4-(trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one
(10o). 36.0 mg, 42% yield. Yellow solid, m.p. 35–36 °C. 1H NMR (500 MHz, CDCl3) δ 8.23 (comp, 5H), 7.63 (d,
J = 8.3 Hz, 2H), 6.99 – 6.91 (comp, 2H), 5.89 – 5.83 (m, 1H), 3.89 (s, 3H), 2.51 – 2.39 (comp, 3H), 2.33 – 2.24
(m, 1H), 2.00 – 1.87 (comp, 2H). 13C NMR (126 MHz, CDCl3) δ 191.9, 187.4, 164.4, 141.9, 138.6, 133.6, 131.7,
130.5 (q, J = 32.8 Hz), 125.9, 125.4 (q, J = 3.8 Hz), 113.6, 82.0, 55.5, 32.5, 32.4, 23.0. IR (neat) 3326, 2930,
2845, 1663, 1596, 1321, 1243, 1164, 1065, 842 cmꢀ1; HRMS (EI) m/z calculated for C23H18F3N2O3 [M−H]−
427.1275, found: 427.1274.
3-(Cyclopent-1-en-1-yl)-5-(4-methoxybenzoyl)-5-[4-(trifluoromethyl)phenyl]-1,5-dihydro-4H-pyrazol-4-one
(11o). 4.3 mg, 5% yield. Yellow solid, m.p. 67 – 68 °C. 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 9.3, 2.6 Hz,
2H), 7.71 (s, 1H), 7.66 (dd, J = 8.5, 2.5 Hz, 2H), 7.48 (dd, J = 8.5, 2.5 Hz, 2H), 6.92 – 6.76 (comp, 3H), 3.84 (s,
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3H), 2.82 – 2.67 (comp, 2H), 2.61 – 2.42 (comp, 2H), 2.00 – 1.84 (comp, 2H). C NMR (126 MHz, CDCl3) δ
192.8, 187.1, 164.2, 143.6, 140.1, 134.6, 133.6, 131.9, 130.8 (q, J = 34.0 Hz), 127.7, 127.1, 126.3 (q, J = 3.8 Hz),
125.2, 125.1, 114.0, 81.2, 55.6, 34.1, 32.7, 22.2. IR (neat) 3337, 2930, 1725, 1667, 1598, 1323, 1243, 1170,
1120, 1070, 841 cmꢀ1; HRMS (EI) m/z calculated for C23H18F3N2O3 [M−H]− 427.1275, found: 427.1277.
5-Benzoyl-3-phenyl-5-(prop-1-en-2-yl)-1,5-dihydro-4H-pyrazol-4-one (10p). 36.5 mg, 60% yield.20 Yellow
solid, m.p. 39 – 40 °C. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 7.4 Hz, 2H), 8.08 (d, J = 6.7 Hz, 2H), 7.93 (s,
1H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.43 – 7.35 (comp, 3H), 5.27 (s, 1H), 5.20 (s, 1H), 1.91 (s,
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3H). C NMR (126 MHz, CDCl3) δ 192.0, 189.9, 143.7, 140.3, 134.1, 133.4, 130.7, 129.3, 129.0, 128.5, 128.5,
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126.0, 116.7, 84.1, 20.0. IR (neat) 3339, 1727, 1671, 1447, 1229, 692 cmꢀ1; HRMS (ESI) m/z calculated for
C19H16N2O2Na [M+Na]+ 327.1104, found: 327.1098.
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5-Benzoyl-3-(4-methoxyphenyl)-5-(prop-1-en-2-yl)-1,5-dihydro-4H-pyrazol-4-one (10q). 48.1 mg, 72% yield.20
Yellow solid, m.p. 44–45 °C. 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 7.4 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H),
7.74 (s, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.25 (s, 1H), 5.18 (s, 1H),
3.83 (s, 3H), 1.90 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 192.4, 190.0, 160.5, 144.1, 140.5, 134.1, 133.4, 130.7,
128.4, 127.6, 121.6, 116.5, 114.0, 83.9, 55.3, 20.0. IR (neat) 3342, 2934, 1730, 1674, 1251, 1231, 1173, 835, 690
cmꢀ1; HRMS (EI) m/z calculated for C20H17N2O3 [M−H]− 333.1245, found: 333.1251.
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Synthesis of 4ꢀHydroxypyrazoles. The experiments were carried out with both: (a) reaction mixtures
containing 10d + 11d and (b) individual compounds 10d or 11d.
(a) Procedure for the synthesis of 6d from a reaction mixture containing 10d and 11d.
To the reaction mixture after the gold(I)ꢀcatalyzed reaction of 9d that contained 1,5ꢀdihydroꢀ4Hꢀpyrazolꢀ4ꢀones
10d and 11d (156 mg, 0.384 mmol) of in DCE (8.0 mL) benzylamine (49.4 mg, 0.461 mmol) dissolved in DCE
(0.5 mL) was added in one portion under a nitrogen atmosphere. The resulting mixture was stirred at 20 °C for 2
h, and the white precipitate of 6' was formed. The precipitate of 6' was dissolved by adding methanol (5.0 mL);
the solution was filtered through Celite to remove gold particles. Solvents were evaporated, and the obtained
mixture of products 6' and Nꢀbenzylbenzamide was separated by column chromatography using hexanes/ethyl
acetate (v/v 2:1) as the eluent to afford 3-([1,1'-Biphenyl]-4-yl)-5-(cyclopent-1-en-1-yl)-1H-pyrazol-4-ol (6')
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(100 mg, 87% yield) as a white solid; m. p. > 300 °C (decomp.). H NMR (300 MHz, DMSOꢀd6) δ 12.54 (br,
1H), 8.04 – 8.01 (comp, 3H), 7.69 (d, J = 7.3 Hz, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.29 (s,
1H), 2.70 – 2.68 (comp, 2H), 2.49 – 2.47 (comp, 2H), 1.99 – 1.78 (comp, 2H). 13C NMR (126 MHz, DMSOꢀd6)
δ 140.3, 138.7, 136.0, 129.4, 127.8, 127.1, 126.9, 126.3, 126.0, 33.4, 33.3, 22.8. IR (neat) 3246 (br), 1634, 1487,
1269, 1016, 844, 767 cmꢀ1; HRMS (ESI) m/z calculated for C20H19N2O [M+H]+ 303.1492, found: 303.1496.
5-(Cyclopent-1-en-1-yl)-3-phenyl-1H-pyrazol-4-ol (6). 81.3 mg, 90% yield. White solid, m. p. 198 – 200 °C
(decomp.). 1H NMR (500 MHz, CD3OD) δ 7.85 (dd, J = 8.1, 0.9 Hz, 2H), 7.45 – 7.42 (m, 2H), 7.35 – 7.32 (m,
1H), 6.48 (dt, J = 4.2, 2.1 Hz, 1H), 2.78 (ddd, J = 9.8, 4.4, 2.1 Hz, 2H), 2.57 (tdd, J = 7.5, 4.8, 2.4 Hz, 2H), 2.07
– 1.93 (comp, 2H). 13C NMR (126 MHz, CD3OD) δ 136.7, 135.1, 134.3, 131.6, 130.4, 128.7, 128.2, 127.5, 126.1,
32.9, 32.6, 22.4. IR (neat) 3249 (br), 1635, 1482, 1274, 1026, 845 cmꢀ1; HRMS (ESI) m/z calculated for
C14H15N2O [M+H]+ 227.1179, found: 227.1181.
(b) Procedure for the synthesis of 6' from pure 10d.
To a solution of 10d (81.0 mg, 0.200 mmol) in DCE (4.0 mL) benzylamine (25.7 mg, 0.240 mmol) dissolved in
DCE (0.3 mL) was added in one portion under a nitrogen atmosphere. The resulting mixture was stirred at 20 °C
for 2 h. Afterward, DCE was evaporated, and the obtained mixture of products 6' and Nꢀbenzylbenzamide was
separated by column chromatography using hexanes/ethyl acetate (v/v 2:1) as the eluent to afford compound 6'
(54.0 mg, 89% yield). The same procedure was used for the synthesis of 6' from 11d.
GoldꢀCatalyzed Reactions of Propargyl Diazoacetates 14−16.
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(a) General Procedure for the Catalysis by AuCl(C4H8S). To a stirred solution of propargyl diazoacetate
(0.30 mmol) in DCE (2.0 mL) AuCl(C4H8S) (4.8 mg, 0.015 mmol) dissolved in DCE (1.0 mL) was added rapidly
under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 12 h (16) or at 84 °C
for 48 h (14 and 15). Solvent was evaporated and the reaction mixture was purified via flashꢀchromatography
(using gradient hexanes to 9:1 hexanes/ethyl acetate as the eluent) to afford compounds 17 and 18. Reported in
Scheme 8 are isolated yields.
3-Methyl-1-phenylbut-2-en-1-one (17).21 Pale yellow liquid. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.1 Hz,
2H), 7.58 – 7.37 (comp, 3H), 6.75 (s, 1H), 2.21 (s, 3H), 2.02 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 191.5,
156.6, 139.2, 132.3, 128.4, 128.2, 121.2, 28.0, 21.2.
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(3-Methylbut-3-en-1-yn-1-yl)benzene (18).22 Colorless liquid. 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.42 (comp,
2H), 7.39 – 7.29 (comp, 3H), 5.43 (s, 1H), 5.33 (s, 1H), 2.02 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 131.7,
131.6, 128.3, 126.9, 123.3, 122.0, 90.6, 88.5, 23.5.
(b) General Procedure for the Catalysis by AuPicCl2. To a stirred solution of propargyl diazoacetate 14
(81 mg, 0.30 mmol) in DCE (2.0 mL) AuPicCl2 (5.9 mg, 0.015 mmol) dissolved in DCE (1.0 mL) was added
rapidly under a nitrogen atmosphere, and the reaction mixture was stirred at 40 °C for 12 h. Solvent was
evaporated and the reaction mixture was purified via flashꢀchromatography (using gradient 19:1 hexanes/ethyl
acetate to 9:1 hexanes/ethyl acetate as the eluent) to afford 17 (6.7 mg, 14%) and 21 (66.4 mg, 82%).
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(Z)ꢀ3-Methyl-1-phenylbuta-1,3-dien-1-yl 2-Diazo-3-oxobutanoate (21). Yellow oil. H NMR (300 MHz,
CDCl3) δ 7.49 – 7.40 (comp, 2H), 7.35 – 7.27 (comp, 3H), 2.49 (s, 3H), 1.83 (s, 6H). 13C NMR (126 MHz,
CDCl3) δ 190.3, 159.6, 131.8, 128.6, 128.2, 122.2, 89.2, 85.0, 74.7, 29.4, 28.3. IR (neat) 2925, 2142, 1726, 1659,
1246, 1139, 1058, 697 cmꢀ1; HRMS (ESI) m/z calculated for C15H14N2O3Na [M+Na]+ 293.0897, found: 293.0888.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental
1
tables, kinetic experiments details, copies of H and 13C NMR spectra of all compounds, crystallographic reports
(PDF).
Crystallographic data for 4 (CIF)
Crystallographic data for 6ʹ (CIF)
AUTHOR INFORMATION
Corresponding Author
*michael.doyle@utsa.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support for this research from the National Science Foundation (CHE−1533833 and CHEꢀ1464690), The
Welch Foundation (AX−1871), and UTSA is gratefully acknowledged. HQ thanks the China Scholarship
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The Journal of Organic Chemistry
Council for a fellowship. The HRMS used in this research is supported by a grant from the National Institutes of
Health (G12MD007591). We thank W. G. Griffith for extensive mass spectral analyses.
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