N-vinylation and N-allylation of 3,5-disubstituted pyrazoles by N-H insertion of vinylcarbenoids

Article abstract of DOI:10.1515/znb-2015-0115

A vinylcarbenoid approach toward N-functionalization of NH-pyrazoles is presented. The rhodium(II)- catalyzed reaction of methyl styryl-diazoacetate (1) or dimethyl 2-diazoglutaconate (3) with 3,5-disubstituted pyrazoles gave products of carbenoid N-H insertion in high combined yields, although regioselectivity issues posed by the pyrazole or the vinylcarbenoid moiety as well as positional and configurational isomerism concerning the C,C double bond of the latter led to product mixtures. The ambident reactivity of the vinylcarbenoid derived from 1 could be steered by the catalyst: While Rh₂(OAc)₄ yielded products of direct carbenoid insertion preferentially, silver(I) catalysis strongly favored reaction at the vinylogous site of the carbenoid resulting in an N-allylation of the pyrazoles.

Full text of DOI:10.1515/znb-2015-0115

Z. Naturforsch. 2015; 70(10)b: 747–756
Agagia Gill, Udo R. Werz and Gerhard Maas*
N-vinylation and N-allylation of 3,5-disubstituted
pyrazoles by N–H insertion of vinylcarbenoids
DOI 10.1515/znb-2015-0115
Received July 7, 2015; accepted July 29, 2015
or their synthetic equivalents and diazo compounds or
nitrilimines, and several types of ring transformations [3].
A less common approach to pyrazoles starts from
vinyldiazo compounds. The majority of known vinyldiazo
Abstract: A vinylcarbenoid approach toward N-function- compounds are characterized by their facile isomerization
alization of NH-pyrazoles is presented. The rhodium(II)- to 1H-pyrazoles through a thermally induced electrocyclic
catalyzed reaction of methyl styryl-diazoacetate (1) or 1,5-cyclization leading to a 3H-pyrazole, followed by a sig-
dimethyl 2-diazoglutaconate (3) with 3,5-disubstituted matropic shift to yield the aromatic 1H-pyrazole. While this
pyrazoles gave products of carbenoid N–H insertion in long known transformation [4–6] constitutes a conveni-
high combined yields, although regioselectivity issues ent pyrazole synthesis from diversely substituted vinyl-
posed by the pyrazole or the vinylcarbenoid moiety as diazoacetates [7–11], it is often an unwanted side reaction
well as positional and configurational isomerism con- in syntheses based on transition-metal catalyzed carbene
cerning the C,C double bond of the latter led to product transfer reactions from such vinyldiazo compounds to a
mixtures. The ambident reactivity of the vinylcarbenoid broad range of substrates (cyclopropanation, insertion
derived from 1 could be steered by the catalyst: while into N–H, O–H and C–H bonds and more [12]). Diazo com-
Rh2(OAc)4 yielded products of direct carbenoid insertion pounds 1 and 3 are two examples which have recently
preferentially, silver(I) catalysis strongly favored reac- been employed frequently for carbenoid transformations,
tion at the vinylogous site of the carbenoid resulting in an and their isomerization to pyrazoles 2 and 4 (Scheme 1),
N-allylation of the pyrazoles.
respectively, has been noticed on several occasions (for
examples, see refs. [8, 13] for 1 and refs. [9, 10] for 3). As
Keywords: N–H insertion; pyrazoles; transition-metal one would expect, the amount of pyrazole increases, when
catalysis; vinylcarbenoids; vinyldiazo compounds.
the carbenoid transformation is carried out at elevated
temperature or when it is slow at room temperature.
In synthetic work with the styryl-diazoacetate 1, we
observed sometimes the formation of minor products,
which were identified as insertion products of the carbene
moiety of 1 into the N–H bond of the tautomeric forms
of pyrazole 2. This motivated us to explore whether this
reaction behavior could be developed into a synthetically
useful approach to N-vinylpyrazoles; the results of this
study are reported herein.
1 Introduction
1H-Pyrazoles are among the most well-known aromatic
azaheterocycles. Although compounds containing a pyra-
zole ring are not abundant in nature, a variety of bioac-
tive pyrazoles are known [1]. Several pyrazole derivatives
are in therapeutic use, in particular N,C,C-trisubstituted
ones. Furthermore, pyrazole derivatives play a role in crop
protection [2]. In the search of novel pyrazole derivatives
with interesting bioactivities or for other applications,
the synthetic chemist can rely on a range of synthetic
methods, the most prominent of which are the reaction of
1,3-dicarbonyl compounds with hydrazine or substituted
hydrazines, 1,3-dipolar cycloaddition reactions of alkynes
The preparation of N-alkylpyrazoles from NH-
pyrazoles or their deprotonated forms with alkyl electro-
philes or diazomethane has been investigated in numerous
studies (see, e.g. refs. [14–16]), and it has been recognized
that for unsymmetrically substituted pyrazoles the regi-
1
vs. N2 alkylation), which depends on reac-
oselectivity (N
tion conditions, nature of the alkylating reagent, electronic
and steric factors, can often not be controlled satisfactorily
[17]. Some highly regioselective N-alkylations are kown,
however (for examples see refs. [18–22]).
*Corresponding author: Gerhard Maas, Institute of Organic
Chemistry I, University of Ulm, 89081 Ulm, Germany,
Fax: +49 (0)731 5022803, E-mail: gerhard.maas@uni-ulm.de
Agagia Gill and Udo R. Werz: Institute of Organic Chemistry I,
University of Ulm, 89081 Ulm, Germany
InsertionofcarbenemoietiesintotheN–Hbondofpyra-
zoles appears as another viable approach to N-substituted
pyrazoles. Although there is ample precedence for the
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ꢀA. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoids
R
of styryl-diazoacetate 1 were conducted at 0 °C rather
CO2Me
(∆)
than at elevated temperatures. To compensate for the
increased reaction times, a larger amount (4.4–5.6 mol%)
than usual of the catalyst, dirhodium(II) tetraacetate,
was applied.
N2
N
R
N
CO2Me
H
1: R = Ph
3: R = CO2Me
2: R = Ph
4: R = CO2Me
From the reaction of styryl-diazoacetate 1 and pyra-
zole 5 at 0 °C, catalyzed by Rh2(OAc)4, four products of
carbene insertion into the N–H bond of the pyrazole could
be isolated after column chromatography in a combined
yield of about 83 % (Scheme 2). The two major products are
the expected carbene insertion product (E-6a, 43 %) and
its double-bond shifted positional isomer (Z-6b, 18 %). In
addition, pyrazole E-7a was obtained, which results from
the so-called vinylogous reactivity of the metal-carbene
complex derived from diazoacetate 1. The fourth product
is most likely the carbene insertion product Z-7a (see
below for the structural assignment).
The vinylogous reactivity of rhodium carbenoids
derived from vinyl-diazoacetates, including those without
[39, 40] and those with [29, 32, 41, 42] a substituent at
the vinyl terminus, is known and has been discussed.
Among other factors, this vinylogous carbenoid reactiv-
ity is favored with bulky substrates and bulky ligands
on the rhodium catalyst [29, 32], furthermore by the use
of diruthenium(I,I) [43] and silver catalysts. Hu [41] and
Davies [44] have reported, that the switch from Rh(II)- to
Ag(I)-catalyzed reactions of vinyl-diazoacetates strongly
enhances the vinylogous over the carbenoid reactiv-
ity. Thus, the high regioselectivity of the dirhodium(II)
tetraacetate catalyzed O–H insertion with various primary
alcohols at the carbenic site of the vinylcarbenoid is com-
pletely reversed in favor of the vinylogous site when the
reaction is catalyzed by silver(I) triflate. With aniline as
the substrate, the regioselectivity change is less expressed
[44]. A DFT computational study has revealed that the
Scheme 1:ꢀIsomerization of vinyldiazo compounds 1 and 3 into
1H-pyrazoles 2 and 4.
effective carbenoid insertion into N–H bonds of primary
and secondary amines by transition-metal catalyzed reac-
tions of diazo compounds (for selected papers, see refs.
[23–27]) including styryl-diazoester 1 [28], analogous
N–H insertion reactions of azoles are rare. With NH-
pyrroles or NH-indoles, the electrophilic metal-carbene
intermediates prefer to react at ring positions C-2 and
C-3 [29–32]; the rhodium(II)-catalyzed N–H insertion of
bis(methoxycarbonyl)carbene with 3-methylindole [33],
an intramolecular analog thereof [34] and the reaction
of methoxycarbonyl(trifluoromethyl)carbene with indole
[35], all three occurring as low-yielding side-reactions, are
exceptions. The N-(tert-butyl)hydroxylamine promoted,
rhodium(II)-catalyzed insertion of the carbene unit of a
styryl-diazoacetate into the N–H bond of 3-methylindole
has been reported and has been extended to tryptophane
labelling in proteins [36, 37].
In this paper, we show that vinyl-diazoacetates can
be used for a carbenoid insertion into the N-H bond of
pyrazoles to give N-vinyl and/or N-allyl substituted pyra-
zoles and we uncover the regioselectivity issues of these
transformations.
2 Results and discussion
We have studied intermolecular carbenoid N–H inser- vinylogous reaction proceeds through silver(I) vinylcar-
tion reactions of the two vinyl-diazoacetates 1 and 3 with bene intermediates and not on a Lewis acid-catalyzed
two NH-pyrazoles, namely the symmetrical 3,5-diphenyl- pathway [44].
1H-pyrazole (5) and the unsymmetrically substituted
In fact, when the reaction of diazoester 1 and pyra-
methyl 5-phenyl-1H-pyrazole-3-carboxylate (2). Only in the zole 5 was catalyzed with silver(I) triflate, the amount of
case of pyrazole 2, which can exist in two tautomeric NH the vinylogous carbene insertion product E-7a increased
forms, a regioselectivity issue is present and indeed gave significantly (51 % yield after chromatographic work-up;
rise to the formation of N1 and N2 substitution products. It 77 % yield based on consumed pyrazole 5), and the direct
should be noted at this point that 2 exists as the 3-CO2Me- carbene insertion products were not found (Scheme 2).
5-Ph-tautomer in the solid state [38].
Under the reaction conditions (refluxing dichlorometh-
ane, excess of 1), a considerable amount of the diazo com-
pound underwent cycloisomerization to give pyrazole 2.
The rhodium(II)-catalyzed reaction of styryl-diazoac-
etate 1 and the unsymmetrically substituted pyrazole 2 at
0 °C furnished the N–H insertion products E-8a and E-8b
in high combined yield but with modest regioselectivity in
2.1 Reactions of styryl-diazoacetate 1
In preliminary experiments, we found that better product
yields were obtained when the carbenoid reactions
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A. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoidsꢂ
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Scheme 2:ꢀRh(II)- or Ag(I)-catalyzed reactions of styryl-diazoacetate 1 and pyrazole 5.
Scheme 3:ꢀReactions of styryl-diazoacetate 1 with pyrazole 2.
favor of the 5-phenylpyrazole-3-carboxylate isomer (E-8a: medium combined yield after chromatographic work-up
E-8b ꢀ=ꢀ 1.5) (Scheme 3). When the reaction was catalyzed (Scheme 4). Besides, a mixture of unidentified decompo-
with silver(I) triflate, the vinylogous carbenoid reaction sition products of the diazo compound was formed.
was triggered again and the regioselectivity of the N–H
insertion was reversed in favor of the 3-phenylpyrazole-
5-carboxylate isomer (E-9b: E-9a ꢀ=ꢀ 5.4). From the amount 2.2 Reactions with dimethyl
of pyrazole 2 recovered after the reaction, it can be con-
2-diazoglutaconate (dimethyl
cluded that ~40 % of diazoester 1 had undergone isomeri-
2-diazopent-3-enedioate) (3)
zation to form pyrazole 2 under the reaction conditions.
Since pyrazole 2 is formed from styryl-diazoacetate The rhodium(II)-catalyzed reaction of diazodiester 3 with
1 by thermal 1,5-electrocyclization, it should be possible 3,5-diphenylpyrazole (5) yielded the carbenoid N–H inser-
to obtain the products of the subsequent carbenoid N–H tion product Z-10 in excellent yield (Scheme 5). From the
insertion directly from 1 in a one-pot reaction, provided reaction of 3 with the unsymmetrical pyrazole 4, the anal-
that the second reaction step can kinetically compete with ogous insertion products Z-11a and Z-11b were obtained in
the first one. When diazoester 1 was treated with a cata- a high combined yield (83 %) (Scheme 5). The two N-sub-
lytic amount of Rh2(OAc)4 in refluxing 1,2-dichloroethane, stituted pyrazole isomers are formed with a higher regi-
the carbenoid pyrazole N–H insertion products E-8a oselectivity (Z-11a: Z-11b ꢀ=ꢀ 2.6) than in the case of N–H
(24 %) and E-8b (34 %) were indeed obtained in a insertion with styryl-diazoacetate 1; it appears that the
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750ꢀ ꢀA. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoids
Scheme 4:ꢀRh(II)-catalyzed decomposition of styryl-diazoacetate 1.
Scheme 5:ꢀRh(II)-catalyzed reactions of pyrazoles 4 and 5 and diazoacetate 3.
higher electrophilicity of the rhodium carbene complex
derived from 3 is responsible for the increased selectivity.
The structure of the carbene moiety in 10 and 11 is
the same in all cases. A double bond shift to the inserting
carbon atom has occurred, resulting in an N-vinylation of
the pyrazole. The Z-configuration of the olefinic double
bond is confirmed by a crystal structure analysis of Z-11b
and NOE experiments on Z-11a (see below).
2.3 Structural assignments
Several structural aspects of the new pyrazoles have to be
considered. X-ray crystal structure determinations of E-8a
and Z-11b, shown in Figs. 1 and 2, indicate the substitu-
tion sites in the pyrazole ring and the double bond con-
figuration in the vinylic or allylic side chain for these two
compounds.
Fig. 1:ꢀMolecular structure of E-8a in the solid state (ortep plot).
Only one of the two symmetry-independent molecules in the unit
cell is shown. Torsion angles (deg); the values for the other mol-
ecule are given after the slash: C2–C3–C9–C10 –38.0(8)/–38.2(8),
C3–N1–C4–C15 121.2(6)/123.7(6), C2–C1–C7–O1 5.5(9)/3.6(8).
Characteristic NMR chemical shifts of some of the
1
prepared pyrazoles are shown in Fig. 3. In the H NMR
spectra, the E configuration of the 1,2-disubstituted Cꢀ=ꢀC
bond of 6a, 7a, 8a, 8b, 9a, 9b is indicated by the large
3
value of the olefinic J coupling constant (15.7–16.0 Hz); double bond in compounds Z-6b, Z-10, Z-11a and Z-11b is
3
in Z-7a the J(cis) coupling constant amounts to only 11.4 less obvious from the NMR data. However, the observation
Hz. On the other hand, the configuration at the N-vinyl of a NOE correlation between the CH2 and the pyrazole-H
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is hampered mainly because two protons of the allyl
moiety are covered by signals of the phenyl protons. The
presence of an acrylate rather than a styryl moiety is indi-
cated by the large chemical shift difference for the olefinic
carbon atoms (δ ꢀ=ꢀ 119.5 and 145.4 ppm, Δδ ꢀ=ꢀ 25.9 ppm;
Δδ ~11 pm is expected for styryl carbon atoms, see Fig. 3).
The high chemical shift of the allylic proton (δ ꢀ=ꢀ 7.47 ppm)
is unusual, but does not differ much from the value
found for E-9b; it appears that in both cases, a conforma-
tion around the C(pyrazole)–C(allyl) bond is fixed which
exposes the allylic C–H bond to the deshielding areas of
magnetic anisotropy of the phenyl and/or pyrazole rings.
The substitution pattern of the pyrazole ring, i. e. the
regioselectivity of the carbenoid N–H insertion, can be
derived without doubt from the chemical shift of the pyra-
zole proton, which is deshielded in the CHꢀ=ꢀC–CO2Me as
compared to the CHꢀ=ꢀC–Ph environment. Similarly, the 13C
signal of the imine-type carbon atom is shielded when a
phenyl group is attached and deshielded when a CO2Me
groupisattached,comparedtothephenyl-substitutedcase.
For both arguments, the data of Z-11b, the crystal structure
of which was determined, can serve as a reference.
Fig. 2:ꢀMolecular structure of Z-11b in the solid state (ortep plot).
Torsion angles (deg): C2–C3–C13–C14 –2.0(3), N1–N2–C4–C9
112.8(2), C2–C1–C11–O5 –4.5(3).
protons of 11a is expected only for the Z-configuration
of the olefinic double bond and an almost perpendicu-
lar conformation at the N–Colefin bond (compare Fig. 2 for
Z-11b). By analogy to Z-11a and Z-11b, the same configura- 3 Conclusion
tion is also assumed for 6b.
The identification of pyrazole Z-7a is based on several In this study we have shown that vinyl-diazoacetates
arguments. While the composition as a carbene insertion 1 and 3 undergo an effective rhodium(II)-catalyzed carbe-
product is secured by mass spectra and elemental analy- noid insertion into the N–H bond of pyrazoles. However,
sis, the positions of Ph and CO2Me at the allyl moiety are mixtures of several isomers were formed and had to
not immediately obvious from the 1H and 13C NMR spectra be separated, which are the result of several selectivity
and furthermore, the signal assignment by 2D techniques issues. Thus, regioisomeric pyrazoles are formed when the
6.65/103.7
Ph
6.67/103.8
Ph
Ph
Ph
6.65/103.6
Ph
Ph
N
N
N N
MeOOC
6.46/123.2
Ph
5.83/123.0
5.65/63.2
6.03/62.9
7.47/58.1
Ph
N N
CO2Me
7.57/146.1
6.85/134.6
7.30/145.4 5.98/119.5
Ph
COOMe
E-6a
E-7a
Z-7a
6.88/109.3
7.22/108.7
6.87/109.3
Ph
7.19/108.6
Ph
COOMe
MeOOC
Ph
MeOOC
Ph
COOMe
N
N
N N
N
N
N
N
MeOOC
MeOOC
Ph
Ph
5.76/64.0
6.54/65.5
7.23/64.0
6.06/63.6
6.88/122.5
6.76/122.3
7.64/123.1
≈7.50/144.7
6.44/135.7
6.69/135.6
5.77/123.9
5.83/145.8
Ph
E-8a
Ph
E-8b
COOMe
COOMe
E-9b
E-9a
Fig. 3:ꢀSelected 1H/13C NMR chemical shifts (δ/ppm, in CDCl3) of some pyrazoles.
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752ꢀ ꢀA. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoids
pyrazole substrate is unsymmetrically substituted, and the diffractometer. Software for structure solution and refine-
vinylcarbenoid brings in additional regioselectivity prob- ment: Shelxs/l-97 [50]; molecule plots: Ortep-3 [51].
lems, as it displays both the expected carbenoid and the In the refinement procedure, the hydrogen atoms were
vinylogous carbenoid reactivity. In addition, the C,C double placed in geometrically calculated positions and treated
bond in the vinylcarbenoid part introduces E,Z isomerism as riding on their bond neighbors in the refinement.
as well as positional isomerism. In the silver(I) triflate cata- Further details are provided in Table 1.
lyzed reaction of styryl-diazoacetate 1, on the other hand,
CCDC 1409521 (E-8a) and 1409522 (Z-11b) contain the
the complexity is reduced, because the vinylogous reactiv- supplementary crystallographic data for this paper. These
ity dominates by far over the direct carbenoid N–H inser- data can be obtained free of charge from The Cambridge
tion, and for the specific combination of 1 and pyrazole 2, Crystallographic Data Centre via www.ccdc.cam.ac.uk/
the regioselectivity at the pyrazole ring is also increased.
data_request/cif.
4.4 Reactions with styryl-diazoacetate 1
4 Experimental section
4.4.1 Rh(II)-catalyzed reaction of diazoester 1 with
4.1 General information
3,5-diphenyl-1H-pyrazole (5)
1H and 13C NMR spectra were recorded on a Bruker Avance A solution of pyrazole 5 (660 mg, 3.00 mmol) and
400 spectrometer (1H: 400.13 MHz; 13C: 100.62 MHz); δ styryl-diazoacetate 1 (606 mg, 3.00 mmol) in dichlo-
values are reported in ppm and coupling constants are romethane (20 mL) was cooled at 0 °C and Rh2(OAc)4
expressed in Hertz (Hz). The signal of the solvent was used
Table 1:ꢀCrystal structure data for E-8a and Z-11b.
as an internal standard: δ(CHCl3) ꢀ=ꢀ 7.26 ppm, δ(CDCl3) ꢀ=ꢀ
77.0 ppm. When necessary, 13C signal assignments were
ꢁ
E-8a
ꢁ
Z-11b
derived from C,H COSY, HSQC and HMBC spectra. IR
spectra: Bruker Vector 22; wavenumbers (cm–1) and inten-
sities (vs ꢀ=ꢀ very strong, s ꢀ=ꢀ strong, m ꢀ=ꢀ medium, w ꢀ=ꢀ weak,
br ꢀ=ꢀ broad) are given. Elemental analyses: elementar vario
MICRO cube; values are given in percent. Mass spectra:
Finnigan MAT, SSQ-7000 (CI mode, 100 eV). Melting
Formula
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
C22H20N2O4
ꢃ
ꢃ
C18H18N2O6
358.34
0.31 ꢃ×ꢃ 0.23 ꢃ×ꢃ 0.15
190(2)
triclinic
P 1
Mr
376.40
Cryst. size, mm3
Temperature (K)
Crystal system
Space group
0.31 ꢃ×ꢃ 0.15 ꢃ×ꢃ 0.10ꢃ
190(2)
orthorhombic
Pna21
19.011(2)
10.825(1)
18.954(3)
90
90
90
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
–
points were determined on a Büchi melting point B-540 a, Å
7.051(2)
11.615(3)
11.965(3)
70.45(3)
75.12(3)
78.81(3)
886.2(4)
2
b, Å
apparatus. All reactions were carried out under an argon
atmosphere, solvents were dried by standard methods
and stored under argon. Column chromatography was
performed on silica gel 60 (Merck, 0.063–0.200 mm).
c, Å
α, deg
β, deg
γ, deg
V, Å3
Z
3900.7(9)
8
D
calcd., g cm–3
1.282
1.343
4.2 Materials
μ(MoKα), cm–1
F(000), e
0.089
0.102
1584
376
(E)-Methyl 2-diazo-4-phenylbut-3-enoate (1) [45], methyl
5-phenyl-1H-pyrazole-3-carboxylate (2) [46] and 3,5-
hkl range
((sinθ)max, deg
22, 12, 22
25.03
8, 13, 14
25.02
diphenyl-1H-pyrazole (5) [47, 48] were prepared by pub- Refl. measured
27288
8428
Refl. unique/Rint
)
3458/0.082
509
2960/0.0542
238
lished procedures. (E)-Dimethyl 4-diazopent-2-enedioate
(3) was prepared by analogy to the diethyl ester [49].
Param. refined
R(F)/wR(F2)a
(all reflexions)
x(Flack)
0.0744/0.1253
0.0738/0.0823
b
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
–
GoF (F2)a
1.010
0.45/–0.20
0.852
4.3 X-ray structure determinations
Δρfin (max/min), e Å–3
0.19/–0.16
Suitable crystals were obtained by crystallization from
2
aR(F) ꢃ=ꢃ Σ||Fo| – |Fc||/Σ|Fo|; wR(F2) ꢃ=ꢃ [Σw(Fo2 – Fc2)2/Σw(Fo )2]1/2
;
GoF ꢃ=ꢃ [Σw(Fo –Fc2)2/(nobs–nparam)]1/2; w ꢃ=ꢃ [σ2(Fo ) + (aP)2 + bP]–1, where
2
2
ethyl acetate-cyclohexane (1:4) (for E-8a) or ethyl acetate
(for Z-11b). Data collection was performed on a Stoe IPDS P ꢃ=ꢃ (Max(Fo , 0) + 2Fc2)/3; bcould not be determined reliably.
2
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(66 mg, 0.15 mmol, 5 mol%) was added. The mixture 1714 (vs), 2947 (w), 3059 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.73 (s, 3 H,
was stirred at 0 °C until N2 evolution had ceased and the OCH3), 5.83 (dd, 3J ꢀ=ꢀ 15.7 Hz, 4J ꢀ=ꢀ 1.4 Hz, 1 H, ꢀ=ꢀCHCO2Me),
3
4
diazo compound was consumed (22 h, IR control). The 6.03 (dd, J ꢀ=ꢀ 6.3 Hz, J ꢀ=ꢀ 1.0 Hz, 1 H, NCH), 6.65 (s, 1 H,
3
3
solvent was evaporated in vacuo and the residue was CHpz), 7.27–7.46 (m, 13 H, CHPh), 7.57 (dd, J ꢀ=ꢀ 15.7 Hz, J ꢀ=ꢀ
fractionated by column chromatography (silica gel, ethyl 6.3 Hz, 1 H, NCCHꢀ=ꢀ), 7.89 (d, J ꢀ=ꢀ 4.4 Hz, 2 H, CHPh) ppm.
13
acetate–cyclohexane (1:20) as eluant). The following frac- – C NMR: δ ꢀ=ꢀ 51.7 (OCH3), 62.9 (NCH), 103.7 (CHpz), 123.0
tions were obtained (in the order of decreasing Rf values): (ꢀ=ꢀCHCO2Me), 125.7, 127.6, 127.7, 128.2, 128.5, 128.7, 128.8,
a) unidentified decomposition product(s) of 1 (20 mg); 128.9, 129.1, 130.4, 133.4, 138.3, 145.4, 146.1 (NCCHꢀ=ꢀ), 151.1
b) a yellow powder tentatively assigned as Z-7a (119 mg, (Cꢀ=ꢀN, pz), 166.4 (Cꢀ=ꢀO) ppm. – MS: m/z ꢀ=ꢀ 395 (100 %). –
10 %) which contains minor impurities (1H NMR); c) E-7a Anal. for C26H22N2O2 (394.47): calcd. C 79.16, H 5.62, N 7.10;
(138 mg, 12 % yield) as a yellow powder; d) E-6a (434 mg, found C 79.01, H 5.70, N 6.96.
37 %) as a yellow powder; e) 219 mg of an oily 1:2 mixture
(Z)-Methyl 4-(3,5-diphenyl-1H-pyrazolyl)-4-phenylbut-2-
ꢀ
of E-6a (6 %) and Z-6b (12 %); f) 48 mg (4 %) of Z-6b as enoate (Z-7a): IR (KBr): υ = 693 (s), 761 (s), 872 (m), 11.85
a resinous yellow oil; g) 34 mg of a mixture which after (m), 1208 (s), 1401 (m), 1338 (m), 1461 (m), 1643 (m), 1713 (s),
preparative thin-layer chromatography (ethyl acetate– 2943 (w), 3037 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.62 (s, 3 H, OCH3),
cyclohexane (1:9) as eluant) yielded 20 mg (2 %) of Z-6b 5.98 (d, 3J ꢀ=ꢀ 11.4 Hz, 1 H, CHolef), 6.65 (s, 1 H, CHpz), 7.2–7.6 (m,
and 10 mg (1.5 %) of unconsumed pyrazole 5.
13 H, CHPh), 7.30 (dd, 1 H, CHolef), 7.47 (dd, 1 H, CHallyl), 7.90
(E)-Methyl 2-(3,5-diphenyl-1H-pyrazolyl)-4-phenylbut- (d, J ꢀ=ꢀ 7.4 Hz, 2 HPh) ppm. – 13C NMR: δ ꢀ=ꢀ 51.4 (OCH3), 58,1
ꢀ
3-enoate(E-6a):m.p.123.6–124.1°C.–IR(KBr): υ = 700 (s), (NCH), 103.6 (CHpz), 119.5 (CHolef), 125.6, 126.9, 127.6, 127.7,
759 (s), 771 (s), 808 (w), 885 (w), 956 (w), 974 (m), 1074 (w), 128.54, 128.59, 128.69, 129.1, 130.3, 133.6, 139.8, 145.4 (CHolef),
1125 (w), 1168 (m), 1198 (m), 1263 (m), 1294 (w), 1313 (w), 145.6, 151.0 (Cꢀ=ꢀNpz), 166.0 (Cꢀ=ꢀO) ppm. – MS: m/z ꢀ=ꢀ 395
1372 (w), 1434 (m), 1458 (m), 1481 (m), 1550 (w), 1749 (s), (100 %), 175 (78 %). – Anal. for C26H22N2O2 (394.47): calcd. C
2959 (w), 3028 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.77 (s, 3 H, OCH3), 79.16, H 5.62, N 7.10; found C 78.97, H 5.69, N 7.00.
5.65 (dd, 3J ꢀ=ꢀ 7.6 Hz, 4J ꢀ=ꢀ 0.7 Hz, 1 H, NCH), 6.46 (d, 3J ꢀ=ꢀ 16.0
Hz, 1 H, CHꢀ=ꢀCHPh, 4J not resolved), 6.67 (s, 1 H, CHpz), 6.85
4.4.2 Ag(I)-catalyzed reaction of diazoester 1 with
(dd, 3J ꢀ=ꢀ 16.0 Hz, 3J ꢀ=ꢀ 7.6 Hz, 1 H, NCCHꢀ=ꢀ), 7.24–7.51 (m, 13
pyrazole 5
H, CHPh), 7.89–7.91 (m, 2 H, CHPh) ppm. – 13C NMR: δ ꢀ=ꢀ 53.0
(OCH3), 63.2 (NCH), 103.8 (CHpz), 123.2 (PhCHꢀ=ꢀCH), 125.9,
To a solution of pyrazole 5 (220 mg, 1.00 mmol) and styryl-
126.8, 127.8, 128.2, 128.5, 128.5, 128.8, 129.0, 129.1, 130.3,
diazoacetate 1 (303 mg, 1.50 mmol) in dichloromethane
133.3, 134.6 (CHꢀ=ꢀ), 135.9, 145.8, 151.6, 169.2 (Cꢀ=ꢀO) ppm.
(15 mL) was added silver(I) trifluoromethanesulfonate
– MS: m/z ꢀ=ꢀ 395 (100 %). – Anal. for C26H22N2O2 (394.47):
(38 mg, 0.15 mmol), and the mixture was heated at reflux,
calcd. C 79.16, H 5.62, N 7.10; found C 78.93, H 5.65, N 6.93.
until the diazo compound had been consumed (8 h, IR
(Z)-Methyl 2-(3,5-diphenyl-1H-pyrazolyl)-4-phenylbut-2-
control). After cooling, the solvent was evaporated in
ꢀ
enoate (Z-6b): – IR (KBr): υ = 695 (m), 763 (s), 780 (m),
vacuo. The solid material, which was formed upon addi-
806 (m), ~1028−1080 (medium-strong broad absorption
tion of ethyl acetate–cyclohexane (1:4) to the residue, was
with several bands), 1204 (m), 1264 (s), 1299 (w), 1375 (w),
subjected to column chromatography (silica gel, ethyl
1436 (m), 1463 (m), 1485 (m), 1654 (m), 1725 (s), 2952 (w),
acetate-cyclohexane (1:4)) to furnish: a) 202 mg (51 %
3028 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.43 (d, 3J ꢀ=ꢀ 7.6 Hz, 2 H, CH2),
based on initial 5) of E-7a as a colorless powder, 64 mg
3.64 (s, 3 H, OCH3), 6.83 (s, 1 H, CHpz), 7.06 (d, 2 H, J ꢀ=ꢀ 6.7
(29 %) of 3,5-diphenylpyrazole (5) and 114 mg (38 % based
Hz, CHPh), 7.12–7.27 (m, 4 H, 3 CHPh and ꢀ=ꢀCHCH2), ~7.20–7.45
on 1) of pyrazole 2. The filtrate of the first precipitation
(m, 8 H, CHPh), 7.91–7.93 (m, 2 H, CHPh). – 13C NMR: δ ꢀ=ꢀ 34.4
was chromatographed separately and yielded unidentified
(CH2), 52.5 (OCH3), 103.4 (CHpz), 125.9, 126.7, 127.9, 128.1,
decomposition products of 1 (73 mg), 3,5-diphenylpyrazole
128.6, 128.7, 128.7, 128.8, 130.2 (NCꢀ=ꢀCH), 131.2, 133.0, 137.0,
(5, 10 mg) and pyrazole 2 (3 mg).
143.7 (ꢀ=ꢀCHCH2), 146.5, 152.5, 163.9 (Cꢀ=ꢀO) ppm. – MS: m/z ꢀ=ꢀ
395 (100 %). – Anal. for C26H22N2O2 (394.47): calcd. C 79.16,
H 5.62, N 7.10; found C 79.11, H 5.81, N 6.91.
4.4.3 Rh(II)-catalyzed reaction of diazoester 1 with
(E)-Methyl 4-(3,5-diphenyl-1H-pyrazolyl)-4-phenylbut-
methyl 5-phenyl-1H-pyrazole-3-carboxylate (2)
ꢀ
2-enoate (E-7a): m. p. 150.3–150.9 °C. – IR (KBr): υ = 695 (m),
708 (m), 763 (s), 808 (w), 870 (w), 957 (w), 977 (m), 1039 (m), To a solution of pyrazole 2 (421 mg, 2.08 mmol) and styryl-
1077 (m), 1154 (w), 1195 (m), 1226 (w), 1280 (s), 1346 (w), diazoacetate 1 (421 mg, 2.08 mmol) was added Rh2(OAc)4
1435 (m), 1452 (m), 1462 (m), 1486 (m), 1549 (w), 1644 (w), (39 mg, 88 μmol) in dichloromethane (15 mL), and the
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754ꢀ ꢀA. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoids
mixture was stirred at 0 °C for 19 h. After addition of another trifluoromethanesulfonate (51 mg, 0.2 mmol, 10 mol%)
portion of Rh2(OAc)4 (13 mg, 29 μmol, 5.6 mol % in total), the was added, and the mixture was stirred at 20 °C for 6 days.
mixture was again stirred at 0 °C for 20 h. The solvent was After evaporation of the solvent, the residue was taken up
evaporated and the residue was taken up in ethyl acetate- in ethyl acetate-cyclohexane (1:4), leaving behind 285 mg
cyclohexane (1:2), leaving behind 84 mg of pyrazole 2, which of pyrazole 2 which was filtered off. The filtrate was con-
was filtered off. The filtrate was concentrated and sub- centrated and separated by column chromatography (silica
jected to column chromatography (silica gel, ethyl acetate- gel, ethyl acetate-cyclohexane (1:4)). Four fractions were
cyclohexane (1:2)). Three major fractions were obtained: a) obtained: a) 369 mg (49 %) of E-9b as a yellow oil; b) 52 mg
249 mg (32 %) of E-8b as a yellow oil; b) 385 mg (49 %) of (6.9 %) of E-9a as a yellow powder; 27 mg of a 1:2 mixture of
E-8a as a colorless powder; c) another portion (60 mg, total E-8a (1.2 %) and E-9a (2.4 %); c) another 41 mg of pyrazole
amount 144 mg, “34 %”) of pyrazole 2 as a pale orange solid. 2 as a colorless solid (total amount 326 mg, “81 %”).
(E)-Methyl
1-(1-methoxycarbonyl-3-phenylprop-2-en-
(E)-Methyl 1-(3-methoxycarbonyl-1-phenylprop-2-en-
1-yl)-5-phenyl-1H-pyrazole-3-carboxylate (E-8a): m. p. 118.4– 1-yl)-5-phenyl-1H-pyrazole-3-carboxylate (E-9a): m. p.
ꢀ
ꢀ
υ = 698 (s),
120.5 °C. – IR (KBr): υ = 693 (w), 705 (w), 765 (m), 773 (m), 133.4–134.2 °C. – IR (KBr):
740 (m), 769 (s),
972 (w), 987 (w), 1173 (w), 1190 (w), 1222 (s), 1270 (m), 1386 828 (w), 950 (w), 996 (m), 1010 (m), 1114 (m), 1166 (m),
(w), 1421 (w), 1433 (m), 1456 (m), 1728 (s), 1750 (s), 2953 (w), 1178 (m), 1202 (s), 1215 (s), 1247 (s), 1310 (m), 1354 (m),
3060 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.74 (s, 3 H, OCH3), 3.95 (s, 3 H, 1376 (w), 1418 (m), 1430 (m), 1448 (s), 1471 (m), 1661 (m),
OCH3), 5.67 (dd, 3J ꢀ=ꢀ 7.9 Hz, 4J ꢀ=ꢀ 0.9 Hz, 1 H, NCH), 6.44 (d, 1718 (vs), 2951 (w), 2996 (w), 3133 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ
3
3J ꢀ=ꢀ 15.9 Hz, 1 H, ꢀ=ꢀCHPh), 6.76 (dd, 3J ꢀ=ꢀ 15.9 Hz, 3J ꢀ=ꢀ 7.9 Hz, 3.72 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 5.77 (dd, J ꢀ=ꢀ 15.7
4
3
1 H, NCCHꢀ=ꢀ), 6.88 (s, 1 H, CHpz), 6.27–7.33 (m, 3 H, CHPh), Hz, J ꢀ=ꢀ 1.5 Hz, 1 H, ꢀ=ꢀCHCO2Me), 6.06 (d, J ꢀ=ꢀ 6.3 Hz, 1 H,
7.36–7.38 (m, 2 H, CHPh), 7.41–7.44 (m, 2 H, CHPh), 7.47–7.50 (m, NCH), 6.87 (s, 1 H, CHpz), 7.17–7.19 (m, 2 H, CHPh), 7.24–7.27
3 H, CHPh) ppm. – 13C NMR: δ ꢀ=ꢀ 52.1 (OCH3), 53.2 (OCH3), 64.0 (m, 2 H, CHPh), 7.30–7.32 (m, 3 H, CHPh), 7.43–7.53 (m, 4 H,
(NCH), 109.3 (CHpz), 122.3 (NCCHꢀ=ꢀ), 126.9, 128.5, 128.6, 129.0, 3 CHPh and NCCHꢀ=ꢀ) ppm. – 13C NMR: δ ꢀ=ꢀ 51.8 (OCH3), 52.1
129.3 (2 C), 129.5, 135.6, 135.7 (ꢀ=ꢀCHPh), 143.7, 145.8, 162.7 (OCH3), 63.6 (NCH), 109.4 (CHpz), 123.9 (ꢀ=ꢀCHCO2Me), 127.4,
(Cꢀ=ꢀO), 168.5 (Cꢀ=ꢀO) ppm. – Anal. for C22H20N2O4 (376.41): 128.5, 128.9 (2 C), 129.3 (2 C), 129.4, 137.3, 143.6 (Cꢀ=ꢀN, pz),
calcd. C 70.20, H 5.36, N 7.44; found C 70.22, H 5.36, N 7.57.
(E)-Methyl 1-(1-methoxycarbonyl-3-phenylprop-2-en- m/z ꢀ=ꢀ 377 (100 %). – Anal. for C22H20N2O4 (376.41): calcd. C
1-yl)-3-phenyl-1H-pyrazole-5-carboxylate (E-8b): IR (NaCl): 70.20, H 5.36, N 7.44; found C 70.23, H 5.44, N 6.92.
144.7 (NCCHꢀ=ꢀ), 145.6, 162.8 (Cꢀ=ꢀO), 166.0 (Cꢀ=ꢀO) ppm. – MS:
ꢀ
υ = 693 (3), 737 (m), 762 (s), 823 (m), 877 (m), 917 (w), 965
(E)-Methyl 1-(3-methoxycarbonyl-1-phenylprop-2-en-
(s), 1002 (m), 1029 (m), 1089 (m), ~1170–1280 (broad absorp- 1-yl)-3-phenyl-1H-pyrazole-5-carboxylate (E-9b): IR (NaCl):
tion, several overlapping strong bands), 1335 (s), 1369 (m), υ = 697 (m), 761 (m), 832 (w), 954 (w), 986 (w), 1029 (w),
ꢀ
1447 (br, s), 1506 (m), 1543 (m), 1606 (w), 1654 (w), 1721 (s), 1090 (m), 1170 (m), 1194 (m), 1226 (m), 1262 (s), 1315 (m),
1750 (s), 2850 (m), 2927 (m), 2953 (m), 3003 (m), 3027 (m), 1446 (s), 1495 (m), 1506 (m), 1541 (w), 1659 (m), 1722 (vs),
3061 (m) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.79 (s, 3 H, OCH3), 3.92 (s, 3 2951 (w), 3031 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.74 (s, 3 H, OCH3),
3
4
H, OCH3), 6.54 (dd, 3J ꢀ=ꢀ 8.0 Hz, 4J ꢀ=ꢀ 0.7 Hz, 1 H, NCH), 6.69 3.88 (s, 3 H, OCH3), 5.83 (dd, J ꢀ=ꢀ 15.7 Hz, J ꢀ=ꢀ 1.6 Hz, 1
(d, 3J ꢀ=ꢀ 16.0 Hz, 1 H, ꢀ=ꢀCHPh), 6.88 (dd, 3J ꢀ=ꢀ 15.9 Hz, 3J ꢀ=ꢀ 8.0 H, ꢀ=ꢀCHCO2Me), 7.19 (s, 1 H, CHpz), 7.23 (dd, 3J ꢀ=ꢀ 6.3 Hz, 4J ꢀ=ꢀ
Hz, 1 H, NCCHꢀ=ꢀ), 7.22 (s, 1 H, CHpz), 7.26–7.45 (m, 8 H, CHPh), 1.5 Hz, 1 H, NCH), 7.26–7.45 (m, 8 H, CHPh), 7.64 (dd, 3J ꢀ=ꢀ 15.7
13
7.83–7.85 (m, 2 H, CHPh) ppm. – C NMR: δ ꢀ=ꢀ 52.1 (OCH3), Hz, 3J ꢀ=ꢀ 6.3 Hz, 1 H, NCHꢀ=ꢀ), 7.84–7.86 (m, 2 H, CHPh) ppm.
53.0 (OCH3), 65.5 (NCH), 108.7 (CHpz), 122.5 (NCCHꢀ=ꢀ), 125.8, – 13C NMR: δ ꢀ=ꢀ 51.7 (OCH3), 52.1 (OCH3), 64.0 (NCH), 108.6
126.9, 128.2, 128.3, 128.6, 128.6, 132.3, 133.1, 135.6 (ꢀ=ꢀCHPh), (CHpz), 123.1 (ꢀ=ꢀCHCO2Me), 125.7, 128.0, 128.2, 128.3, 128.6,
136.0, 150.7 (Cꢀ=ꢀN, pz), 160.2 (Cꢀ=ꢀO), 169.2 (Cꢀ=ꢀO) ppm. – MS: 128.7, 132.3, 133.0, 138.0, 145.8 (CHꢀ=ꢀCHCO2Me), 150.6, 160.1
m/z ꢀ=ꢀ 377 (100 %). – Anal. for C22H20N2O4 (376.41): calcd. C (Cꢀ=ꢀO), 166.4 (Cꢀ=ꢀO) ppm. – MS: m/z ꢀ=ꢀ 377 (100 %). – Anal.
70.20, H 5.36, N 7.44; found C 70.03, H 5.35, N 7.30.
for C22H20N2O4 (376.41): calcd. C 70.20, H 5.36, N 7.44; found
C 70.04, H 5.55, N 7.54.
4.4.4 Ag(I)-catalyzed reaction of diazoester 1 with
pyrazole 2
4.4.5 Rh(II)-catalyzed decomposition of
styryl-diazoacetate 1
A solution of pyrazole 2 (404 mg, 2.0 mmol) and
styryl-diazoacetate 1 (404 mg, 2.0 mmol) in dichlo- To a solution of (E)-methyl 2-diazo-4-phenylbut-3-enoate
romethane (20 mL) was cooled at 0 °C, silver(I) (1, 404 mg, 2.0 mmol) in 1,2-dichloroethane (5 mL) was
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A. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoidsꢂ
ꢂ755
added Rh2(OAc)4 (8.84 mg, 20 μmol, 1 mol%) and the and the mixture was stirred at 20 °C for 18 h. After addition
mixture was heated at reflux for 50 min, when the diazo- of another 14 mg (0.032 mmol) of Rh2(OAc)4, the reaction
compound had disappeared (IR control). After cooling to mixture was again stirred at 20 °C for 24 h. The solvent
r.t., the solvent was evaporated in vacuo and the crude was evaporated and the residue was separated by column
product mixture was separated by column chromatog- chromatography (silica gel, ethyl acetate-cyclohexane
raphy (silica gel, ethyl acetate–cyclohexane (1:4)). Three (1:2) to furnish three fractions: a) 118 mg (19 %) of Z-11b as
fractions were obtained: 103 mg of a mixture of uniden- a colorless powder; b) 51 mg of a mixture containing Z-11b
tified decomposition products from 1; b) a yellow oil of (~27 mg, ~4 %); c) 377 mg (60 %) of Z-11a as a colorless
E-8b (127 mg, 34 %); c) a colorless powder of E-8a (89 mg, powder.
24 %).
(Z)-Dimethyl
2-[5-(methoxycarbonyl)-3-phenyl-1H-
pyrazol-1-yl]-pent-2-enedioate (Z-11a): m. p. 97.8–99.2 °C.
ꢀ
– IR (KBr): υ = 699 (m), 763 (s), 782 (s), 812 (w), 884 (w),
4.5 Reactions with (E)-dimethyl 4-diazopent- 947 (w), 990 (m), 1012 (s), 1052 (m), 1117 (m), ~1170–1270
(broad strong absorption with several overlapping bands),
2-enedioate (3)
1385 (s), 1452 (s), 1668 (m), 1733 (vs), 2955 (s), 3003 (m),
4.5.1 (Z)-Dimethyl 2-(3,5-diphenyl-1H-pyrazol-1-yl)pent-
2-enedioate (Z-10)
3137 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.09 (d, 3J ꢀ=ꢀ 7.2 Hz, 2 H, CH2),
3.62 (s, 3 H, CH2COOCH3), 3.66 (s, 3 H, Colef−COOCH3), 3.96
(s, 3 H, Cpz-COOCH3), 7.01 (s, 1 H, CHpz), 7.33–7.39 (m, 6 H,
A solution of diazoester 3 (442 mg, 2.4 mmol), 3,5- 5 CHPh and ꢀ=ꢀCHCH2) ppm. – 13C NMR: δ ꢀ=ꢀ 33.1 (CH2), 52.16
diphenylpyrazole (5, 440 mg, 2.0 mmol) and Rh2(OAc)4 (OCH3), 52.25 (OCH3), 52.72 (OCH3), 108.4 (CHpz), 127.8, 128.7
(31 mg, 70 μmol) in dichloromethane (10 mL) was stirred (MeO2CCꢀ=ꢀCH), 128.8, 129.2, 132.3, 137.2 (ꢀ=ꢀCHCH2), 144.8,
at 0 °C for 45 h. Since the diazo compound was not yet con- 146.7, 162.4 (Cꢀ=ꢀO), 162.5 (Cꢀ=ꢀO), 168.9 (Cꢀ=ꢀO) ppm. – MS:
sumed completely (IR control), another 16 mg (36 μmol, in m/z ꢀ=ꢀ 359 (100 %). – Anal. for C18H18N2O6 (358.35): calcd. C
total 4.4 mol%) of Rh2(OAc)4 was added and the mixture 60.33, H 5.06, N 7.82; found C 60.22, H 5.01, N 7.89.
was heated at reflux for 10 h. The solvent was evaporated
(Z)-Dimethyl
2-[3-(methoxycarbonyl)-5-phenyl-1H-
and ethyl acetate-cyclohexane (1:2) was added to the pyrazol-1-yl]-pent-2-enedioate (Z-11b): m. p. 104.5–106.1 °C.
ꢀ
residue. Crude pyrazole 5 (29 mg) remained undissolved – IR (KBr): υ = 688 (w), 761 (m), 775 (w), 1043 (m), 1084
and was filtered off. The filtrate was subjected to column (m), 1091 (m), 1177 (m), 1205 (m), 1234 (m), 1260 (s), 1353
chromatography (silica gel, ethyl acetate-cyclohexane (w), 1374 (m), 1437 (m), 1452 (m), 1512 (w), 1547 (w), 1664
(1:2)), which yielded Z-10 (708 mg, 94 % based on pyra- (w), 1719 (s), 1729 (s), 1742 (s), 2995 (w) cm–1. – H NMR:
1
3
ꢀ
zole 5) as a yellow oil. – IR (NaCl): υ = 696 (s), 760 (s), 883 δ ꢀ=ꢀ 3.25 (broadened d, J ꢀ=ꢀ 6.8 Hz, 2 H, CH2), 3.70 (s, 3 H,
(w), 919 (w), 956 (m), 989 (m), 1031 (w), 1051 (m), 1083 (w), OCH3), 3.80 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 7.25 (s, 1 H,
1174 (s), 1205 (s), 1263 (br, s), 1378 (m), 1437 (s), 1462 (s), CHpz), 7.33–7.44 (m, 4 H, 3 CHPh and ꢀ=ꢀCHCH2), 7.81–7.83 (m,
13
1486 (s), 1552 (m), 1606 (w), 1664 (m), 1735 (br, s), 2953 (m), 2 H, CHPh) ppm. – C NMR: δ ꢀ=ꢀ 33.2 (CH2), 52.19 (OCH3),
3062 (w) cm–1. – 1H NMR: δ ꢀ=ꢀ 3.28 (d, 3J ꢀ=ꢀ 7.2 Hz, 2 H, CH2), 52.25 (OCH3), 52.67 (OCH3), 108.5 (CHpz), 125.8, 128.6,
3.61 (s, 3 H, OCH3), 3.64 (s, 3 H, OCH3), 6.79 (s, 1 H, CHpz), 128.7, 131.9, 133.4, 134.0 (Cꢀ=ꢀCH), 135.5, 152.4 (Cꢀ=ꢀN, pz),
3
7.28 (t, J ꢀ=ꢀ 7.2 Hz, 1 H, ꢀ=ꢀCHCH2), 7.32–7.44 (m, 8 H, CHPh), 159.3 (Cꢀ=ꢀO), 163.0 (Cꢀ=ꢀO), 169.6 (Cꢀ=ꢀO) ppm. – Anal. for
7.86–7.88 (m, 2 H, CHPh) ppm. – 13C NMR: δ ꢀ=ꢀ 33.4 (CH2), 52.2 C18H18N2O6 (358.35): calcd. C 60.33, H 5.06, N 7.82; found C
(OCH3), 52.5 (OCH3), 103.5 (CHpz), 125.9, 127.7, 128.2, 128.6, 60.25, H 5.17, N 7.78.
128.7, 128.8, 130.0, 132.8 and 133.0 (MeO2CCꢀ=ꢀCH and CPh),
135.6 (ꢀ=ꢀCHCH2), 146.5, 152.8, 163.3 (Cꢀ=ꢀO), 169.5 (Cꢀ=ꢀO) ppm.
– MS: m/z ꢀ=ꢀ 377 (100 %). – Anal. for C22H20N2O4 (376.41):
References
calcd. C 70.20, H 5.36, N 7.44; found C 70.04, H 5.36, N 7.47.
[1] A. Schmidt, A. Dreger, Curr. Org. Chem. 2011, 15, 1423.
[2] C. Lamberth, Heterocycles, 2007, 71, 1467.
[3] B. Stanovnik, J. Svete, Pyrazoles in Science of Synthesis, Vol 12
(Ed.: R. Neier), Thieme Verlag, Stuttgart, 2002, p. 15.
[4] D. W. Adamson, J. Kenner, J. Chem. Soc. 1935, 286.
[5] C. D. Hurd, S. C. Lui, J. Am. Chem. Soc. 1935, 57, 2656.
[6] G. L. Closs, W. Böll, Angew. Chem., Int. Ed. Engl. 1963, 2, 399.
[7] A. Padwa, Y. S. Kulkarni, Z. Zhang, J. Org. Chem. 1990,
55, 4144.
4.5.2 Rh(II)-catalyzed reaction of diazoester 3 with
methyl 5-phenyl-1H-pyrazole-3-carboxylate (2)
A solution of pyrazole 2 (355 mg, 1.76 mmol) and diazoester
3 (388 mg, 2.11 mmol) in dichloromethane (15 mL) was
cooled at 0 °C, Rh2(OAc)4 (28 mg, 0.063 mmol) was added
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ꢀꢀꢀꢁ
756ꢀ ꢀA. Gill et al.: N-substituted pyrazoles by N–H insertion of vinylcarbenoids
[8] J. R. Manning, H. M. L. Davies, Org. Synth. 2007, 84, 334.
[9] M. B. Supurgibekov, V. M. Zakharova, J. Sieler, V. A. Nikolaev,
Tetrahedron Lett. 2011, 52, 341.
[10] M. B. Supurgibekov, D. Cantillo, C. O. Kappe, G. K. S. Prakash,
V. A. Nikolaev, Org. Biomol. Chem. 2014, 12, 682.
[11] D. J. Babinski, H. R. Aguilar, R. Still, D. E. Frantz, J. Org. Chem.
2011, 76, 5915.
[12] H. M. L. Davies, Curr. Org. Chem. 1998, 2, 463.
[13] H. M. L. Davies, D. K. Hutcheson, Tetrahedron Lett. 1993, 34,
7243.
[14] M. R. Grimmett, K. H. R. Lim, R. T. Weavers, Aust. J. Chem. 1979,
32, 2203.
[15] N. Malhotra, B. Fält-Hansen, J. Becher, J. Heterocyclic Chem.
1991, 28, 1837.
[16] I. Almena, E. Díez-Barra, A. de la Hoz, J. Ruiz,
A. Sánchez-Migallón, J. Elguero, J. Heterocycl. Chem. 1998, 35,
1263.
[17] A. Schmidt, A. Dreger, Curr. Org. Chem. 2011, 15, 2897.
[18] L.-R. Wen, S.-W. Wang, M. Li, W.-Y. Qi, X.-L. Zhang, H.-Z. Yang,
J. Chinese Chem. Soc. (Taipai, Taiwan) 2005, 52, 1021.
[19] V. Montoya, J. Pons, V. Branchadell, J. Ros, Tetrahedron 2005,
61, 12377.
[20] H. Walter, C. Corsi, J. Ehrenfreund, C. Lambert, H. Tobler,
WO 2006045504 A1 20060504, 2006.
[21] V. L. M. Silva, A. M. S. Silva, D. C. G. A. Pinto, P. Rodríguez,
M. Gómez, N. Jagerovic, L. F. Callado, J. A. S. Cavaleiro,
J. Elguero, J. Fernández-Ruiz, Arkivoc 2010 (x), 226.
[22] P. A. Bradley, P. D. de Koning, K. R. Gibson, Y. C. Lecouturier,
M. C. MacKenny, I. Morao, C. Poinsard, T. J. Underwood, Synlett
2010, 21, 873.
[23] E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris, D. Haigh,
C. J. Moody, N. D. Pearson, J. B. Sanghera, J. Chem. Soc., Perkin
Trans. 1, 1996, 2879.
[24] C. J. Moody, Angew. Chem. Int. Ed. 2007, 46, 9148.
[25] Q.-H. Deng, H-W. Xu, A. W.-H. Yuen, Z.-J. Xu, C.-M. Che, Org.
Lett. 2008, 10, 1529.
[26] E. C. Lee, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 12066.
[27] S.-F. Zhu, Q.-L. Zhou, Acc. Chem. Res. 2012, 45, 1365.
[28] O. Pavlyuk, H. Teller, M. C. McMills, Tetrahedron Lett. 2009, 50,
2716.
[29] Y. Lian, H. M. L. Davies, Org. Lett. 2010, 12, 924.
[30] W.-W. Chan, S.-H. Yeung, Z. Zhou, A. S. C. Chan, W.-Y. Yu, Org.
Lett. 2010, 12, 604.
[31] M. B. Johansen, M. A. Kerr, Org. Lett. 2010, 12, 4956.
[32] Y. Lian, H. M. L. Davies, Org. Lett. 2012, 14, 1934.
[33] R. Gibe, M. Kerr, J. Org. Chem. 2002, 67, 6247.
[34] B. Zhang, A. G. H. Wee, Chem. Commun. 2008, 4837.
[35] I. E. Tsyshchuk, D. V. Vorobyeva, A. S. Peregudov, S. N. Osipov,
Eur. J. Org. Chem. 2014, 2480.
[36] J. M. Antos, M. B. Francis, J. Am. Chem. Soc. 2004, 126, 10256.
[37] J. M. Antos, J. M. McFarland, A. T. Iavarone, M. B. Francis, J. Am.
Chem. Soc. 2009, 131, 6301.
[38] G. Zhou, Y. An, J. Han, M. Ge, Y. Xing, Acta Crystallogr. 2007,
E63, o4474.
[39] H. M. L. Davies, E. Saikali, W. B. Young, J. Org. Chem. 1991, 56,
5696.
[40] H. M. L. Davies, B. Hu, E. Saikali, P. R. Bruzinski, J. Org. Chem.
1994, 59, 4535.
[41] Y. Yue, Y. Wang, W. Hu, Tetrahedron Lett. 2007, 48, 3975.
[42] X. Xu, P. Y. Zavalij, W. Hu, M. P. Doyle, J. Org. Chem. 2013, 78,
1583–1588; and lit. cit.
[43] Y. Sevryugina, B. Weaver, J. Hansen, J. Thompson, H. M. L.
Davies, M. A. Petrukhina, Organometallics 2008, 27, 1750.
[44] J. H. Hansen, H. M. L. Davies, Chem. Science 2011, 2, 457.
[45] H. M. L. Davies, T. J. Clark, H. D. Smith, J. Org. Chem. 1991, 56,
3817.
[46] A. Tanaka, T. Terasawa, H. Hagihara, Y. Sakuma, N. Ishibe, M.
Sawada, H. Takasugi, H. Tanaka, J. Med. Chem. 1998, 41, 2390.
[47] L. Knorr, P. Duden, Ber. Dtsch. Chem. Ges. 1893, 26, 111.
[48] N. Kitajima, K. Fujisawa, C. Fujimoto, Y. Moro-oka, S. Hashi-
moto, T. Kitagawa, K. Toriumi, K. Tatsumi, A. Nakamura, J. Am.
Chem. Soc. 1992, 114, 1277.
[49] H. M. L. Davies, D. M. Clark, D. B. Alligood, G. R. Eiband,
Tetrahedron 1987, 43, 4265.
[50] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112.
[51] L. J. Farrugia, J. Appl. Cryst., 2012, 45, 849.
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