An approach to 2,4-substituted pyrazolo[1,5-a]pyridines and pyrazolo[1,5-a]azepines by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201300901

The ring-closing metathesis (RCM) reactions of dienylpyrazoles have been employed in the synthesis of pyrazolo[1,5-a]pyridine and pyrazolo[1,5-a]azepine derivatives. Based on this approach, the diastereoselective synthesis of potential peptidomimetics containing four amino acid residues with the second (i+1) and third (i+2) fragments having been substituted by bicyclic frameworks is described. The N-allylation of readily available 3,5-substituted pyrazoles followed by ring-closing metathesis of the resulting 1,5-diolefinic derivatives leads to the formation of 2,4-substituted pyrazolo[1,5-a]pyridines and pyrazolo[1,5-a]azepines in high yields. The application of this protocol to the diastereoselective synthesis of potential peptidomimetics is described. Copyright

Full text of DOI:10.1002/ejoc.201300901

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FULL PAPER
DOI: 10.1002/ejoc.201300901
An Approach to 2,4-Substituted Pyrazolo[1,5-a]pyridines and
Pyrazolo[1,5-a]azepines by Ring-Closing Metathesis
Santos Fustero,*[a,b] Raquel Román,[a] Amparo Asensio,[a] Miguel A. Maestro,[c]
José L. Aceña,[d] and Antonio Simón-Fuentes*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Metathesis / Peptidomimetics / Nitrogen heterocycles
The ring-closing metathesis (RCM) reactions of dienylpyr-
azoles have been employed in the synthesis of pyrazolo[1,5-
a]pyridine and pyrazolo[1,5-a]azepine derivatives. Based on
this approach, the diastereoselective synthesis of potential
peptidomimetics containing four amino acid residues with
the second (i+1) and third (i+2) fragments having been sub-
stituted by bicyclic frameworks is described.
Introduction
The chemistry of pyrazoles is attracting increasing inter-
est due to the broad range of applications shown by a large
number of pyrazole derivatives. The pyrazole ring is present
in a number of small molecules that possess a wide range
of biological activities that can be exploited in the fields of
agriculture and pharmaceuticals. Moreover, some pyrazoles
constitute scaffolds in supramolecular and polymer chemis-
try as well as in the food industry.[1]
Among pyrazole-fused bicyclic substructures, the pyr-
azolo[1,5-a]pyridine framework is especially relevant be-
cause it is present in many pharmacologically active com-
pounds, for example, in inhibitors of p38 kinase,[2] dopa-
minergics,[3] inhibitors of herpes simplex viruses,[4] non-
xanthine adenosine A1 receptor antagonists,[5] and melaton-
ine receptor ligands[6] (Figure 1). This substructure has also
been proposed as a stable bioisoster of the indole nucleus
to circumvent problems arising from the metabolic instabil-
ity of indoles.[7]
Figure 1. Pharmacologically active pyrazolo[1,5-a]pyridine deriva-
tives.
The most generally useful approach to achieving this sys-
tem involves the [3+2] cycloaddition reactions of N-amino-
pyridinium salts with substituted alkynes.[2–7,8] Other meth-
ods have also been reported.[2a,9] Charrette and co-workers
recently reported a new methodology for the synthesis of 2-
substituted pyrazolo[1,5-a]pyridines through direct cascade
alkenylation/cyclization reactions.[10] In contrast, methods
for the preparation of pyrazolo[1,5-a]azepine derivatives are
very scarce. In fact, to the best of our knowledge, only two
procedures dealing with the synthesis of this class of bicy-
clic heterocycles have been reported to date.[11] The first one
allowed the formation of two substituted pyrazolo[1,5-a]-
azepines through the cycloaddition reaction of a diazo-
ketone and an activated acetylene,[11a] and the second one
involved an intramolecular acylation of the C-5 pyrazole
carbon by a Parham-type cyclization of a pyrazole-1-
carboxylic acid.[11b]
[a] Departamento de Química Orgánica, Universitat de València,
46100 Burjassot, Valencia, Spain
E-mail: santos.fustero@uv.es
antonio.simon@uv.es
www.santosfustero.com
[b] Laboratorio de Moléculas Orgánicas, Centro de Investigación
Príncipe Felipe,
46012 Valencia, Spain
[c] Departamento de Química Fundamental, Universidade da
Coruña,
15071 A Coruña, Spain
[d] Department of Organic Chemistry I, University of the Basque
Country,
As a continuation of our investigation of new strategies
for the preparation of biologically active simple pyr-
azoles,[12] we focused our attention on the synthesis of pyr-
20018 San Sebastian, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300901.
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azolo[1,5-a]pyridine (1) and pyrazolo[1,5-a]azepine (2) de- Subsequent RCM of 7a and 8a by using 5 mol-% of the
rivatives (Scheme 1). Based on the ring-closing metathesis Hoveyda–Grubbs’ catalyst [Ru-III] in dichloromethane
(RCM) reaction, we have investigated new synthetic path- (DCM; for 7a) or in dichloroethane (DCE; for 8a) at reflux
ways to accessing these fused heterobicyclic compounds. afforded the bicyclic alcohols 1a and 2a in excellent
Despite the utility of RCM for the preparation of medium- yields,[19] which on dehydration with a solution of 1 m HCl
and large-sized carbo- and heterocyclic compounds,[13] only in THF at reflux gave 2-(2-furyl)pyrazolo[1,5-a]pyridine
a few reports on the application of this methodology to the (1c) and 2-(2-furyl)pyrazolo[1,5-a]azepine (2c) in excellent
synthesis of fused bicyclic heteroaromatic compounds have yields. Cyclization of the dienylpyrazole 5b was also found
been published,[14] and none on the synthesis of pyr- to be feasible when the reaction mixture was heated at re-
azolo[1,5-a]pyridine or pyrazolo[1,5-a]azepine derivatives.
flux in DCM for 4 h in the presence of the [Ru-III] catalyst
leading to ethyl 5,8-dihydro-4H-pyrazolo[1,5-a]azepine-2-
carboxylate (2b) in good yield. The yield increased substan-
tially (up to 80%) when the process was carried out under
microwave irradiation at 80 °C with a significant drop in
reaction time (1 h).
Synthesis of Potential Peptidomimetics 9 and 10
Scheme 1. Synthetic strategy to pyrazolo[1,5-a]pyridine and pyr-
azolo[1,5-a]azepine derivatives.
In the last two decades, research in the field of peptid-
omimetics has gained considerable momentum due to their
potential use as precursors of small molecules that display
more favorable therapeutic properties than natural peptides.
The design and synthesis of conformationally restricted
peptidomimetics is an important approach towards im-
proving the potency, selectivity, and metabolic stability of
peptide-based drugs.[20] In this sense, some bicyclic ring sys-
Results and Discussion
Synthesis of Pyrazolo[1,5-a]pyridines 1 and Pyrazolo[1,5-
a]azepines 2
Synthetic strategies for accessing the target fused bicyclic tems, such as azabicycloalkane amino acids, have proven
compounds 1 and 2 are depicted in Schemes 2 and 3. Thus, to be versatile and effective scaffolds that mimic secondary
3,5-disubstituted pyrazoles 4a and 4b were obtained in peptide structures.[21] Incidentally, bicyclic templates restrict
good yields by condensation of the previously prepared 1,3- conformations by a combination of structural constraints
dicarbonyl compounds 3a and 3b,[15] respectively, with an- and steric interactions, which are influenced by the stereo-
hydrous hydrazine following standard procedures chemistry of the scaffold, the presence of substituents, and
(Scheme 2, Pathway A).[16] The best result for the N-allyl- the frame size in particular.
ation of 4b was obtained by using NaH as a base followed
On the basis of the success of our strategy for the synthe-
by the addition of allyl bromide. The diolefinic pyrazole 5b sis of 5,6- and 5,7-fused pyrazole derivatives by RCM, we
was obtained as the only product in 66% yield.[17] However, extended this protocol to the diastereoselective synthesis of
under these reaction conditions, 4a led to a mixture of re- bicyclic ring amino acids 9,10aa and 9,10ab (Scheme 3).
gioisomers 5aa and 5ab in 80% yield, the major component These structures mimic peptides containing four amino acid
(93%) being the undesired 5ab. To improve the yield of 5aa, residues, the second (i+1) and third (i+2) fragments having
the N-allylation of 4a was carried out under the reaction been substituted by bicyclic frameworks.
conditions described by Moreno-Mañas et al.[18] for the al-
The retrosynthetic analysis of 9 and 10 from the formyl-
lylation of uracils. The catalytic complex [Pd2(dba)3]/dppb pyrazole 6a is depicted in Scheme 3. The key step is the
was added to a solution of 4a in THF, followed by the ad- stereoselective creation of a stereocenter at C-4. In prin-
dition of allyl acetate. After warming at 60 °C for 18 h, a ciple, one of the most versatile methods for the asymmetric
mixture of 5aa and 5ab (ratio 4:1) was formed in almost synthesis of amines is the 1,2-addition of nucleophiles such
quantitative yield. Both regioisomers were easily separated as organometallic reagents to chiral imines.[22] However,
and purified by flash chromatography, and characterized by when imines react with basic nucleophiles, electron-with-
spectral analysis. NOESY experiments allowed the unam- drawing substituents on nitrogen are necessary to activate
biguous assignment of their structures.
the C=N double bond. The tert-butanesulfinyl group has
The ethoxycarbonyl group of 5aa was then converted proved to be an ideal N-substituent for the nucleophilic ad-
into aldehyde 6a in a two-step sequence involving reduction dition to imines, providing a highly efficient approach to
to a primary alcohol (90% yield) followed by oxidation of the asymmetric synthesis of many different types of amines.
the hydroxylic function with activated MnO2 in acetonitrile This group can be easily introduced by condensation of a
(75% yield; Scheme 2, Pathway B). Dienylpyrazoles 7a and carbonyl compound with enantiomerically pure tert-but-
8a, precursors of the 5,6- and 5,7-pyrazoles, were obtained anesulfinamide in the presence of a Lewis acid.[23]
in high yields by the addition of vinyl- and allylmagnesium
The condensation of 6a with (R)-tert-butanesulfinamide
bromide, respectively, to a solution of 6a in THF at 0 °C. in the presence of 4 equiv. of Ti(OEt)4 led to imine 11a in
2
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Pyrazolopyridines and -azepines by Ring-Closing Metathesis
Scheme 2. Synthesis of pyrazolo[1,5-a]pyridine and pyrazolo[1,5-a]azepine derivatives.
almost quantitative yield (Scheme 4). Following Ellman and 13aa and (RS,R)-13ab was obtained in 84% yield (13aa/
co-workers’ procedure,[24] when allylmagnesium bromide 13ab = 4:1; Method A), which were separated by flash
was added to a CH2Cl2 (DCM) solution of 11a at –60 °C, chromatography.[25] On the other hand, the diastereoselec-
a mixture of two diastereoisomeric dienylpyrazoles (RS,S)- tive allylation of 11a with allyl bromide and indium in a
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S. Fustero, A. Simón-Fuentes et al.
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Scheme 3. Strategy for the synthesis of peptidomimetics 9 and 10.
Scheme 4. Synthesis of dienylpyrazoles 12 and 13.
NaBr saturated aqueous solution at room temperature led group. As the l-alanine residue is present in the side-chain
to the diastereoisomer (RS,S)-13aa as the sole product (50% at C-4 in the final products 9 and 10, another strategy in-
yield at 75% conversion; Method B).[26] Furthermore, ad- volving the substitution of the tert-butanesulfinyl group in
dition of allylzinc bromide to 11a using hexamethylphos- 12 and 13 with N-Boc-l-alanine was adopted. The tert-but-
phoramide (HMPA) as solvent at room temperature gave anesulfinyl group was removed by adding a solution of HCl
the diastereoisomer (RS,R)-13ab as the only product in 58% in dioxane to a solution of the respective dienylpyrazole 12
yield (Method C).[27]
or 13 in MeOH at room temperature, followed by stirring
For the addition of the vinylic chain, the best dia- for 30 min. A solution of N-Boc-l-alanine in DMF was
stereomeric results were obtained (12aa/12ab = 4:96) when then added followed by the coupling agent 2-(1H-benzotri-
a previously prepared solution of dimethylzinc and vinyl- azol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
magnesium bromide in THF was added to a THF solution (HBTU) and diisopropylethylamine (DIEA) as base. As ex-
of 11a at –78 °C (Method D).[28] When applying Ellman pected, the respective dienylpyrazoles 14 and 15 were ob-
and co-workers’ reaction conditions, the chemical yield was tained in high yields (Scheme 5). The relative configuration
good (98%), but the selectivity was very low, 12aa/12ab = of the newly created stereocenter (C-α of the side-chain at-
1.5:1 (Method A; Scheme 4).
tached to the C-5 of the pyrazole ring) in 15aa was assigned
With the dienylpyrazoles 12 and 13 in hand, the RCM S by means of X-ray crystallography.[29]
reaction was conducted. Despite many attempts under dif-
Compounds 14 and 15 underwent the RCM reaction in
ferent reaction conditions, the outcome was not satisfac- the presence of 5 mol-% Hoveyda–Grubbs’ catalyst [Ru-III]
tory, probably due to the presence of the tert-butanesulfinyl leading to the bicyclic fused pyrazole derivatives 16 and 17
4
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Pyrazolopyridines and -azepines by Ring-Closing Metathesis
hydropyridine ring in 9aa was determined by X-ray crystal-
lographic analysis (Figure 2).[30]
Figure 2. ORTEP diagram of (S,S)-9aa.
The propensity of 9aa, 9ab, 10aa, and 10ab to mimic
peptide structures is currently under investigation. Prelimi-
nary results seem to indicate the presence of an intramolec-
ular hydrogen bond between the amide proton on the sub-
stituent on the pyrazole ring and the carbonyl oxygen of
the amido group in the substituent of the tetrahydropyr-
idine ring in 9aa, which could mimic a β-turn secondary
structure. Further applications of the new substrates are
currently being investigated in our laboratory.
Conclusions
We have developed a new approach to the synthesis of
2,4-substituted pyrazolo[1,5-a]pyridines and pyrazolo-
[1,5-a]azepines from readily available 3,5-disubstituted 1H-
pyrazoles. These pyrazoles were N-allylated to afford 1,5-
diolefinic intermediates, which underwent ring-closing me-
tathesis (RCM) in the presence of 5 mol-% of the Hoveyda–
Grubbs’ catalyst to afford the target products in excellent
yields. This approach has been applied to the diastereoselec-
tive synthesis of four potential peptidomimetics containing
four amino acid residues with the second (i+1) and third
(i+2) fragments having been substituted by bicyclic frame-
works.
Scheme 5. Synthesis of peptidomimetics 9 and 10.
(Scheme 5). The cyclization reactions of dienyl pyrazoles 14
in DCM at reflux were found to be very efficient resulting
in 16 in excellent yields. However, the dienylpyrazoles 15
did not produce satisfactory results under similar condi-
tions. The best results were obtained when 15 was heated at
reflux in DCE for 18 h, although the starting materials were
not totally transformed. The C=C double bond in the un-
saturated bicyclic compounds 16 and 17 was then hydrogen-
Experimental Section
General Methods: All reactions were carried out under nitrogen.
ated by treatment with hydrogen in the presence of Pd/C to The solvents were purified prior to use: THF was distilled from
sodium/benzophenone and dichloromethane was distilled from cal-
cium hydride. The reactions were monitored with the aid of TLC
on 0.25-mm precoated silica gel plates. Visualization was carried
out with UV light. Flash column chromatography was performed
on silica gel 60 (particle size 0.040–0.063 mm) with the solvents
indicated in each case. Melting points were measured with a Büchi
B-540 apparatus. 1H and 13C NMR spectra were recorded with
300 MHz Bruker AC300 and 400 MHz Bruker Avance spectrome-
ters. Chemical shifts are given in ppm (δ) and are referenced to the
residual proton resonances of the solvents. Coupling constants (J)
afford 18 and 19 in good yields. To introduce the second
amino acid unit at C-2 of the pyrazole ring, the furyl group
must be oxidized. Thus, ozone was bubbled into colorless
solutions of 18 and 19 in MeOH at –78 °C until the blue
color became permanent. Bicyclic carboxylic acids 20 and
21 were formed in high yields. Finally, these compounds
were subjected to condensation with the ethyl glycinate salt
under the same reaction conditions as employed for the in-
troduction of l-alanine to give the final products 9 and 10
in good yields. The S configuration at C-4 in the tetra- are given in Hertz (Hz). The letters m, s, d, t, and q represent
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S. Fustero, A. Simón-Fuentes et al.
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multiplet, singlet, doublet, triplet, and quartet, respectively. The let-
ters br. indicate that the signal is broad.
144.4, 162.9 ppm. HRMS (EI): calcd. for C13H18N2O2 [M]+
234.1368; found 234.1361.
1-Allyl-3-(2-furyl)-1H-pyrazole-5-carbaldehyde (6a):[12b] Yellow oil
(880 mg, 67.5% from 5aa, two steps). 1H NMR (300 MHz,
CDCl3): δ = 5.01–5.13 (m, 4 H, CH2, CH2), 5.85–5.98 (m, 1 H,
Microwave reactions were carried out in a 0.5–2 mL vial with a
Biotage InitiatorTM 2.0 microwave synthesizer. The solutions were
stirred before the irradiation was started and the absorbance of the
solvent was set as “normal”. The reaction time was initiated as
soon the system reached the input temperature, although it took
approximately 2 min to reach it.
1
2
1
CH), 6.38 (dd, J = 3.4, J = 1.9 Hz, 1 H, CH), 6.63 (dd, J = 3.4,
1
2
2J = 0.8 Hz, 1 H, CH), 6.99 (s, 1 H, CH), 7.37 (dd, J = 1.9, J =
0.8 Hz, 1 H, CH), 9.76 (s, 1 H, CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 54.6, 106.9, 111.5, 111.8, 118.5, 132.9, 139.9, 142.7,
144.0, 147.8, 179.8 ppm. HRMS (EI): calcd. for C11H10N2O2 [M]+
202.0742; found 202.0750.
High-resolution mass spectra were recorded with a VGmAutospec
(VG Analytical, Micromass Instruments) by the Universitat de
València Mass Spectrometry Service.
Ethyl 5-(3-Butenyl)-1H-pyrazole-3-carboxylate (4b):[15] Yellow oil
(65%). H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.0 Hz, 3 H,
Addition of Grignard Reagents: The Grignard reagent (1 m in THF,
1.5 mmol) was slowly added to a solution of 6a (203.5 mg,
1.0 mmol) in dry THF (6 mL) cooled to 0 °C. After stirring for 3 h
(TLC), a saturated NH4Cl solution was added and the crude mix-
ture was extracted with EtOAc. The combined organic extracts
were washed with brine, dried with anhydrous Na2SO4, concen-
trated under vacuum, and purified by flash chromatography.
1
CH3), 2.35 (dt, 1J = 8.1, 2J = 6.6 Hz, 2 H, CH2), 2.75 (t, J = 7.2 Hz,
2 H, CH2), 4.31 (q, J = 7.0 Hz, 2 H, CH2), 4.93–5.03 (m, 2 H,
CH2), 5.71–5.84 (m, 1 H, CH), 5.65 (s, 1 H, CH), 8.71 (br., 1 H,
NH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.6, 25.9, 33.4, 61.3,
106.8, 116.2, 137.4, 162.3 ppm. HRMS (EI): calcd. for C10H14N2O2
[M]+ 194.1059; found 194.1055.
1-Allyl-3-(2-furyl)-5-(1-hydroxy-2-propenyl)-1H-pyrazole
(7a):
Flash chromatography (n-hexane/EtOAc, 2:1). Pale-yellow oil
Ethyl 1-Allyl-3-(2-furyl)-1H-pyrazole-5-carboxylate (5a): A mixture
of allyl acetate (1.75 mL, 16.2 mmol) in THF (10 mL), bis(di-
benzylideneacetone)palladium (201.4 mg, 0.22 mmol), and 1,4-
bis(diphenylphosphanyl)butane (184.3 mg, 0.432 mmol) was added
to a solution of 4a (1Ј103 g, 5.4 mmol) in THF (15 mL). After heat-
ing at 60 °C for 18 h, the mixture was extracted with EtOAc and
washed with H2O. The organic layer was dried and concentrated.
The residue was purified by flash chromatography (n-hexane/
EtOAc, 4:1) to afford 5aa as a pale-yellow oil (1.03 g, 78%) and
5ab as a yellow oil (259.0 mg, 20%). For 5aa: 1H NMR (300 MHz,
CDCl3): δ = 1.32 (t, J = 7.2 Hz, 3 H, CH3), 4.28 (q, J = 7.2 Hz, 2
H, CH2), 5.02 (d, J = 17.3 Hz, 1 H, CHH), 5.08–5.15 (m, 3 H,
CHH, CH2), 5.91–6.04 (m, 1 H, CH), 6.39 (dd, 1J = 3.4, 2J =
1.7 Hz, 1 H, CH), 6.62 (d, J = 3.4 Hz, 1 H, CH), 6.99 (s, 1 H, CH),
7.38 (d, J = 1.7 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 14.6, 54.6, 61.6, 106.6, 108.3, 111.7, 117.9, 133.5, 142.5, 143.2,
148.3, 159.7 ppm. HRMS (EI): calcd. for C13H14N2O3 [M]+
1
(172.5 mg, 75%). H NMR (300 MHz, CDCl3): δ = 4.70 (ddt, 1J
2
3
1
2
= 16.2, J = 5.3, J = 1.5 Hz, 1 H, CHH), 4.78 (ddt, J = 16.2, J
3
1
2
= 5.6, J = 1.5 Hz, 1 H, CHH), 4.97 (dd, J = 17.1, J = 1.1 Hz, 1
H, CHH), 5.10 (dd, J = 10.6, J = 1.5 Hz, 1 H, CHH), 5.16 (br.,
1
2
1
2
1 H, CH), 5.22 (dd, J = 10.2, J = 1.1 Hz, 1 H, CHH), 5.31 (dd,
1J = 17.1, J = 1.1 Hz, 1 H, CHH), 5.84–5.96 (m, 1 H, CH), 5.98–
2
6.07 (m, 1 H, CH), 6.31 (s, 1 H, CH), 6.34 (dd, 1J = 3.4, 2J =
1
2
1.9 Hz, 1 H, CH), 6.53 (dd, J = 3.4, J = 0.8 Hz, 1 H, CH), 7.33
(dd, J = 1.9, J = 0.8 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 52.4, 66.4, 101.9, 105.6, 111.2, 116.6, 117.8, 133.3,
136.9, 141.6, 142.8, 144.2, 148.5 ppm. HRMS (EI): calcd. for
C13H14N2O2 [M]+ 230.1015; found 230.1011.
1
2
1-Allyl-3-(2-furyl)-5-(1-hydroxy-3-butenyl)-1H-pyrazole (8a): Flash
chromatography (n-hexane/EtOAc, 1:1). Pale-yellow oil (231 mg,
1
95%). H NMR (300 MHz, CDCl3): δ = 2.17 (s, 1 H, OH), 2.57–
2.62 (m, 2 H, CH2), 4.72 (dd, 1J = 7.4, 2J = 7.3 Hz, 1 H, CH),
1
246.0960; found 246.0964. For 5ab: H NMR (300 MHz, CDCl3):
4.80–4.84 (m, 2 H, CH2), 5.01 (dd, 1J = 17.2, 2J = 1.1 Hz, 1 H,
δ = 1.34 (t, J = 7.2 Hz, 3 H, CH3), 4.35 (q, J = 7.2 Hz, 2 H, CH2),
4.95–4.99 (m, 3 H, CHH, CH2), 5.13 (d, J = 10.6 Hz, 1 H, CHH),
1
2
CHH), 5.13–5.18 (m, 2 H, CH2), 5.19 (dd, J = 17.2, J = 1.3 Hz,
1 H, CHH), 5.73–5.87 (m, 1 H, CH), 5.91–6.04 (m, 1 H, CH), 6.39
(dd, 1J = 3.4, 2J = 1.9 Hz, 1 H, CH), 6.58 (dd, 1J = 3.4, 2J = 0.7 Hz,
1 H, CH), 7.38 (dd, 1J = 1.9, 2J = 0.7 Hz, 1 H, CH) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 41.2, 52.8, 65.1, 101.6, 106.0, 111.6,
117.7, 119.5, 133.8, 133.9, 142.1, 143.3, 145.8, 149.1 ppm. HRMS
(EI): calcd. for C14H16N2O2 [M]+ 244.1212; found 244.1193.
2
5.87–5.99 (m, 1 H, CH), 6.44 (dd, 1J = 3.4, J = 1.9 Hz, 1 H, CH),
1
6.53 (d, J = 3.4 Hz, 1 H, CH), 6.95 (s, 1 H, CH), 7.45 (dd, J =
2
1.9, J = 1.1 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 14.8, 54.6, 61.5, 108.4, 110.0, 111.9, 118.3, 132.6, 135.6, 143.5,
162.5 ppm. HRMS (EI): calcd. for C13H14N2O3 [M]+ 246.0960;
found 246.0962.
Ring-Closing Metathesis of 7a, 8a and 5b: The second-generation
Hoveyda–Grubbs’ catalyst (5 mol-%) was added to a solution of 7a
(202 mg, 0.88 mmol) [or 8a (0.60 mg, 0.61 mmol) or 5b (100 mg,
0.43 mmol)] in DCE (0.05 m) (or DCM), and the mixture was
heated at reflux for 2 h for 7a and 8a (5b was heated under micro-
waves at 80 °C for 1 h). The solvent was evaporated and the crude
mixture was purified by flash chromatography (n-hexane/EtOAc,
1:1, for 1a and 2a; n-hexane/EtOAc, 2:1, for 2b).
Ethyl 1-Allyl-5-(3-butenyl)-1H-pyrazole-3-carboxylate (5b): NaH
(18.4 mg, 0.77 mmol) was added portionwise to a solution of 4b
(124Ј1 mg, 0.64 mmol) in DMF (5 mL) at 0 °C, and the mixture
was stirred for 20 min. Then allyl bromide (68 μL, 0.77 mmol) was
added and the mixture was stirred for 3 h. The solvent was concen-
trated under vacuum and the crude mixture extracted with EtOAc.
After washing with H2O, the organic layer was dried and concen-
trated. Flash chromatography (n-hexane/EtOAc, 4:1) afforded 5b
1
as a pale-yellow oil (98.8 mg, 66%). H NMR (300 MHz, CDCl3):
2-(2-Furyl)-4,7-dihydropyrazolo[1,5-a]pyridin-4-ol (1a): White solid
1
2
1
δ = 1.32 (t, J = 7.1 Hz, 3 H, CH3), 2.36 (dt, J = 7.5, J = 6.6 Hz, (176 mg, 99%); m.p. 160–162 °C. H NMR (300 MHz, CDCl3): δ
2 H, CH2), 2.62 (t, J = 7.5 Hz, 2 H, CH2), 4.33 (q, J = 7.1 Hz, 2 = 4.63–4.81 (m, 2 H, CH2), 5.28 (d, J = 3.6 Hz, 1 H, CH), 6.07–
6.19 (m, 2 H, CH, CH), 6.53 (dd, 1J = 3.4, J = 1.8 Hz, 1 H, CH),
1
2
1
2
H, CH2), 4.73 (dt, J = 5.3, J = 1.7 Hz, 2 H, CH2), 4.94 (dd, J =
1
2
16.1, 2J = 0.8 Hz, 1 H, CHH), 4.98 (d, J = 9.7 Hz, 1 H, CHH), 6.62 (s, 1 H, CH), 6.72 (dd, J = 3.4, J = 0.8 Hz, 1 H, CH), 7.56
(dd, J = 1.8, J = 0.8 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz,
1
2
1
2
1
2
5.02 (dd, J = 16.1, J = 1.5 Hz, 1 H, CHH), 5.15 (dd, J = 9.7, J
= 0.9 Hz, 1 H, CHH), 5.70–5.82 (m, 1 H, CH), 5.84–5.95 (m, 1 H, CDCl3): δ = 48.3, 61.8, 101.7, 107.3, 112.7, 124.1, 127.7, 143.7
CH), 6.57 (s, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
14.8, 25.2, 32.4, 53.0, 61.2, 107.9, 116.1, 118.1, 132.7, 136.9, 143.0,
145.4, 150.3 ppm. HRMS (EI): calcd. for C11H10N2O2 [M]+
202.0742; found 202.0739.
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30901
/KAP1
Date: 17-09-13 19:40:20
Pages: 12
Pyrazolopyridines and -azepines by Ring-Closing Metathesis
2-(2-Furyl)-5,8-dihydro-4H-pyrazolo[1,5-a]azepin-4-ol (2a): Yellow
oil (118.6 mg, 84%). H NMR (300 MHz, CDCl3): δ = 2.57–2.60
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 21.4, 52.9, 56.9,
105.4, 107.7, 110.4, 116.4, 131.9, 136.6, 141.2, 142.8, 146.7,
149.4 ppm. HRMS (EI): calcd. for C15H19N3O2S [M]+ 305.1197;
found 305.1192.
1
1
2
3
(m, 3 H, CH2, OH), 4.77 (ddd, J = 17.3, J = 4.7, J = 1.2 Hz, 1
1
2
3
H, CHH), 4.93 (ddd, J = 17.3, J = 4.1, J = 1.7 Hz, 1 H, CHH),
1
2
5.07 (dd, J = 5.5, J = 5.1 Hz, 1 H, CH), 5.65–5.82 (m, 2 H, CH,
CH), 6.35 (s, 1 H, CH), 6.39 (dd, J = 3.3, J = 1.7 Hz, 1 H, CH),
Addition of Organometallic Reagents: Method A: Grignard rea-
gent;[24] method B: allyl bromide/In;[26] method C: allyl bromide/
Zn;[26] method D: Grignard reagent/Me2Zn.[28]
1
2
1
2
1
2
6.55 (dd, J = 3.3, J = 0.6 Hz, 1 H, CH), 7.37 (dd, J = 1.7, J =
0.6 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 36.0,
50.7, 64.8, 101.6, 105.8, 111.6, 123.3, 127.5, 142.3, 142.4, 146.3,
149.1 ppm. HRMS (EI): calcd. for C12H12N2O2 [M]+ 216.0899;
found 216.0907.
(RS)-N-{(1S)-1-[1-Allyl-3-(2-furyl)-1H-5-pyrazolyl]-2-propenyl}-
tert-butylsulfinamide (12aa): Pale-yellow oil (177 mg, 59 %,
method A; 11.7 mg, 3.9%, method D). [α]2D5 = –55.1 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.23 (s, 9 H, 3 CH3),
3.48 (d, J = 5.1 Hz, 1 H, NH), 4.84 (m, 2 H, CH2), 5.02–5.09 (m,
2 H, CH2), 5.21–5.25 (m, 1 H, CH), 5.29–5.35 (m, 2 H, CH2), 5.93–
6.12 (m, 2 H, 2 CH), 6.43 (dd, 1J = 3.4, 2J = 1.8 Hz, 1 H, CH),
Ethyl 5,8-Dihydro-4H-pyrazolo[1,5-a]azepin-2-carboxylate (2b):
1
Pale-yellow oil (70.8 mg, 80%). H NMR (300 MHz, CDCl3): δ =
1
2
1.34 (t, J = 7.0 Hz, 3 H, CH3), 2.34 (dt, J = 3.4, J = 2.1 Hz, 2
H, CH2), 2.92 (t, J = 5.8 Hz, 2 H, CH2), 4.33 (q, J = 7.0 Hz, 2 H,
CH2), 4.87 (d, J = 2.5 Hz, 2 H, CH2), 5.66–5.77 (m, 2 H, CH, CH),
6.55 (s, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.8,
23.2, 28.1, 50.5, 61.2, 107.7, 121.7, 131.8, 141.9, 144.9, 162.9 ppm.
HRMS (EI): calcd. for C11H14N2O2 [M]+ 206.1055; found
206.1059.
1
2
6.44 (s, 1 H, CH), 6.63 (dd, J = 3.4, J = 0.7 Hz, 1 H, CH), 7.42
(dd, J = 1.8, J = 0.7 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 22.5, 52.4, 53.5, 56.2, 102.7, 105.6, 111.2, 117.6, 118.4,
132.9, 136.3, 141.7, 142.5, 143.3, 148.6 ppm. HRMS (FAB): calcd.
for C17H24N3O2S [M + H]+ 334.1584; found 334.1596.
1
2
(RS)-N-{(1R)-1-[1-Allyl-3-(2-furyl)-1H-5-pyrazolyl]-2-propenyl}-
tert-butylsulfinamide (12ab): Pale-yellow oil (117 mg, 39 %,
method A; 282 mg, 94%, method D). [α]2D5 = –51.9 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.20 (s, 9 H, 3 CH3),
3.56 (d, J = 2.7 Hz, 1 H, NH), 4.76–4.93 (m, 2 H, CH2), 5.18–5.39
Dehydration of 1a and 2a: A solution of 1 m HCl (0.50 mmol) was
added to a solution of 1a (50 mg, 0.247 mmol) [or 2a (55 mg,
0.255 mmol)] in THF (3 mL) at room temperature and the mixture
was heated at reflux for 1 h. The crude mixture was extracted with
EtOAc. The combined organic extracts were washed with H2O,
then with brine, and dried with anhydrous Na2SO4. The solvent
was removed under vacuum and the crude mixture was purified by
flash chromatography (n-hexane/EtOAc, 3:1).
1
(m, 3 H, CH, CH2), 5.87–6.03 (m, 2 H, CH2), 6.40 (dd, J = 3.3,
1
2
2J = 1.8 Hz, 1 H, CH), 6.43 (s, 1 H, CH), 6.60 (dd, J = 3.3, J =
1
2
0.6 Hz, 1 H, CH), 7.39 (dd, J = 1.8, J = 0.6 Hz, 1 H, CH) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 22.4, 51.9, 52.3, 55.7, 102.3,
105.5, 111.0, 117.4, 118.5, 133.0, 135.4, 141.5, 142.5, 143.0,
148.3 ppm. HRMS (FAB): calcd. for C17H24N3O2S [M + H]+
334.1584; found 334.1597.
2-(2-Furyl)pyrazolo[1,5-a]pyridine (1c): White solid (44.6 mg, 97%);
m.p. 75–77 °C. 1H NMR (300 MHz, CDCl3): δ = 6.47 (dd, 1J =
2
1
3.4, J = 1.9 Hz, 1 H, CH), 6.68 (s, 1 H, CH), 6.70 (dd, J = 6.8,
2J = 1.3 Hz, 1 H, CH), 6.81 (dd, J = 3.4, J = 0.8 Hz, 1 H, CH),
7.06 (ddd, J = 8.8, J = 6.8, J = 1.1 Hz, 1 H, CH), 7.45 (dd, J
= 8.8, J = 1.0 Hz, 1 H, CH), 7.48 (dd, J = 1.8, J = 0.8 Hz, 1 H,
CH), 8.41 (dd, 1J = 6.8, 2J = 1.0 Hz, 1 H, CH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 92.3, 106.3, 110.5, 110.9, 116.9, 122.7,
127.5, 140.2, 141.6, 144.7, 147.7 ppm. HRMS (EI): calcd. for
C11H8N2O [M]+ 184.0637; found 184.0633.
1
2
1
2
3
1
(RS)-N-{(1S)-1-[1-Allyl-3-(2-furyl)-1H-5-pyrazolyl]-3-butenyl}-
tert-butylsulfinamide (13aa): Pale-yellow oil (200.9 mg, 67 %,
2
1
2
method A; 57 mg, 50% at 75% conversion, method B). [α]2D5
=
1
–93.6 (c = 1.1, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.14 (s,
9 H, 3 CH3), 2.57–2.62 (m, 2 H, CH2), 3.58 (d, J = 3.9 Hz, 1 H,
NH), 4.47–4.53 (m, 1 H, CH), 4.80 (d, J = 5.3 Hz, 2 H, CH2), 5.01
(d, J = 17.1 Hz, 1 H, CHH), 5.13 (d, J = 10.4 Hz, 1 H, CHH), 5.17
(d, J = 10.6 Hz, 2 H, CH2), 5.60–5.74 (m, 1 H, CH), 5.88–6.01 (m,
2-(2-Furyl)pyrazolo[1,5-a]azepine (2c): Yellow oil (44.5 mg, 90%).
1H NMR (300 MHz, CDCl3): δ = 4.73 (d, J = 6.4 Hz, 2 H, CH2),
1
2
1 H, CH), 6.38 (s, 1 H, CH), 6.39 (dd, J = 3.4, J = 1.8 Hz, 1 H,
CH), 6.58 (d, J = 3.4 Hz, 1 H, CH), 7.37 (dd, 1J = 1.8, 2J = 0.8 Hz,
1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 22.9, 41.6, 49.9,
52.8, 56.4, 102.4, 105.9, 111.6, 118.0, 120.4, 133.4, 133.5, 142.1,
143.7, 144.2, 149.1 ppm. HRMS (EI): calcd. for C18H25N3O2S
[M]+ 347.1667; found 347.1670.
1
2
1
2
5.90 (dt, J = 10.2, J = 6.4 Hz, 1 H, CH), 6.24 (dd, J = 20.0, J
= 5.5 Hz, 1 H, CH), 6.28 (dd, 1J = 20.0, 2J = 5.9 Hz, 1 H, CH)
1
2
6.40 (dd, J = 3.4, J = 1.1 Hz, 1 H, CH), 6.44 (s, 1 H, CH), 6.56
(dd, 1J = 3.4, 2J = 0.8 Hz, 1 H, CH), 6.67 (d, J = 11.1 Hz, 1 H,
CH), 7.39 (dd, 1J = 1.9, 2J = 0.8 Hz, 1 H, CH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 49.4, 102.4, 105.5, 111.3, 121.5, 125.4,
127.9, 130.7, 141.2, 141.8, 143.4, 148.8 ppm. HRMS (EI): calcd.
for C12H10N2O [M]+ 198.0793; found 198.0783.
(RS)-N-{(1R)-1-[1-Allyl-3-(2-furyl)-1H-5-pyrazolyl]-3-butenyl}-
tert-butylsulfinamide (13ab): Pale-yellow oil (50.9 mg, 17 %,
method A; 66 mg, 58%, method C). [α]2D5 = –1.4 (c = 1.4, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.12 (s, 9 H, 3 CH3), 2.58–2.67
N-[(RS)-tert-Butylsulfinyl][1-allyl-3-(2-furyl)-1H-5-pyrazolyl]-
methanimine (11a): (R)-(+)-2-Methyl-2-propanesulfinamide
(307 mg, 2.5 mmol) and Ti(OEt)4 (0.8 mL, 3.84 mmol) were added
to a solution of 6a (418 mg, 2.07 mmol) in dry CH2Cl2 (20 mL)
in a round-bottomed flask, and the mixture was stirred at room
temperature for 20 h. Then H2O/ice (10 mL) was added until white
titanium salts precipitated. The suspension was filtered through a
short pad of Celite® and washed with CH2Cl2. The clear solution
was concentrated under vacuum to afford 11a. Yellow oil (620 mg,
98%). [α]2D5 = –95.5 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
1
(m, 2 H, CH2), 3.52 (d, J = 3.6 Hz, 1 H, NH), 4.43 (td, J = 7.1,
2J = 3.8 Hz, 1 H, CH), 4.74–4.89 (m, 2 H, CH2), 4.96 (dd, 1J =
17.2, 2J = 17.1 Hz, 1 H, CHH), 5.02–5.15 (m, 3 H, CHH, CH2),
5.56–5.68 (m, 1 H, CH), 5.87–5.99 (m, 1 H, CH), 6.37 (dd, 1J =
3.4, 2J = 1.5 Hz, 1 H, CH), 6.43 (s, 1 H, CH), 6.56 (d, J = 3.4 Hz, 1
H, CH), 7.35 (d, J = 1.5 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 22.9, 40.8, 50.3, 52.5, 56.5, 102.7, 106.1, 111.6, 117.8,
119.6, 133.4, 133.8, 142.1, 143.5, 143.6, 149.0 ppm. HRMS (EI):
calcd. for C18H25N3O2S [M]+ 347.1667; found 347.1661.
δ = 1.17 (s, 9 H, 3 CH3), 4.91 (d, J = 17.1 Hz, 1 H, CHH), 5.02–
1
5.23 (m, 3 H, CHH, CH2), 5.86–5.99 (m, 1 H, CH), 6.38 (dd, J = Addition of
L
-Alanine: At room temperature, hydrogen chloride
2
3.4, J = 1.9 Hz, 1 H, CH), 6.63 (d, J = 3.4 Hz, 1 H, CH), 6.89 (s, (5.0 equiv., 4 m in dioxane) was added to a solution of sulfinamine
1 H, CH), 7.38 (dd, J = 1.9, J = 0.8 Hz, 1 H, CH), 8.45 (s, 1 H, 12 (143.6 mg, 0.43 mmol) [or 13 (150 mg, 0.43 mmol)] in MeOH
1
2
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30901
/KAP1
Date: 17-09-13 19:40:20
Pages: 12
S. Fustero, A. Simón-Fuentes et al.
50.3, 52.5, 80.8, 101.5, 105.9, 111.6, 117.8, 119.4, 133.3, 133.7,
FULL PAPER
(0.1 m), and the solution was stirred for 30 min (TLC). After re-
moving the solvents, the crude mixture was dissolved in DMF 142.1, 143.5, 144.1, 149.1, 156.0, 172.2 ppm. HRMS (EI): calcd.
(0.1 m) and N-Boc-l-alanine (90 mg, 0.47 mmol), HBTU (328 mg,
0.86 mmol), and DIEA (1.30 mmol, 0.23 mL) were sequentially
added. The solution was stirred for 15 h at room temperature, and
then concentrated under vacuum. The crude mixture was extracted
with EtOAc. The organic extract was washed with citric acid
(3 mL), satd. NaHCO3 (3 mL), and brine, dried with anhydrous
Na2SO4, concentrated under vacuum, and purified by flash
chromatography (n-hexane/EtOAc, 1:1, for 14; n-hexane/EtOAc,
4:1, for 15).
for C22H30N4O4 [M]+ 414.2267; found 414.2252.
Ring-Closing Metathesis of 14 and 15: The second-generation Hov-
eyda–Grubbs’ catalyst (15.4 mg; 0.02 mmol) was added to a solu-
tion of 14 (196.5 mg, 0.49 mmol) [or 15 (202.8 mg, 0.49 mmol)] in
DCM (0.05 m) (or DCE). The mixture was heated at reflux for 18 h
for 14, and for 6 h followed by stirring for 10 h at room temperature
for 15. The solvent was evaporated and the crude mixture was puri-
fied by flash chromatography (n-hexane/EtOAc, 1:2, for 16; n-hex-
ane/EtOAc, 2:1, for 17).
(2S)-2-(N-Boc-amino)-N-{(1S)-1-[1-allyl-3-(2-furyl)-1H-5-pyr-
azolyl]-2-propenyl}propanamide (14aa): White solid (146.5 mg,
85%). [α]2D5 = –132.4 (c = 1.0, CHCl3); m.p. 85–87 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.35 (d, J = 6.9 Hz, 3 H, CH3), 1.42 (s, 9
H, 3 CH3), 4.13 (dq, 1J = 6.9, 2J = 6.8 Hz, 1 H, CH), 4.80–4.88
(m, 3 H, CH2, NH), 5.04–5.32 (m, 4 H, 2 CH2), 5.74–5.78 (m, 1
(2S)-2-(N-Boc-amino)-N-[(4S)-2-(2-furyl)-4,7-dihydropyrazolo-
[1,5-a]pyridin-4-yl]propanamide (16aa): White solid (164.5 mg,
90%). [α]2D5 = +22.8 (c = 0.9, CHCl3); m.p. 88–90 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.39 (s, 9 H, 3 CH3), 1.36 (d, J = 8.1 Hz,
3 H, CH3), 4.17–4.22 (m, 1 H, CH), 4.63–4.78 (m, 2 H, CH2), 5.13
(br., 1 H, NH), 5.77–5.91 (m, 2 H, CHH, CH), 6.04–6.08 (m, 1 H,
CHH), 6.41 (s, 1 H, CH), 6.42 (dd, 1J = 3.3, 2J = 1.8 Hz, 1 H,
CH), 6.58 (dd, 1J = 3.3, 2J = 0.6 Hz, 1 H, CH), 6.88 (br., 1 H,
NH), 7.39 (dd, 1J = 1.8, 2J = 0.6 Hz, 1 H, CH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 18.4, 28.1, 42.1, 46.8, 50.1, 80.2, 100.1,
105.8, 111.2, 123.1, 123.7, 138.7, 141.8, 143.8, 148.6, 155.3,
172.3 ppm. HRMS (FAB): calcd. for C19H25N4O4 [M + H]+
373.1870; found 373.1852.
1
H, CH), 5.93–6.06 (m, 2 H, 2 CH), 6.38 (s, 1 H, CH), 6.44 (dd, J
2
1
2
= 3.4, J = 1.8 Hz, 1 H, CH), 6.61 (dd, J = 3.4, J = 0.9 Hz, 1 H,
CH), 6.65 (br., 1 H, NH), 7.42 (dd, 1J = 1.8, 2J = 0.9 Hz, 1 H,
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 17.3, 28.2, 46.1, 50.1,
52.2, 80.5, 102.4, 105.6, 111.2, 116.5, 117.5, 133.0, 134.4, 141.7,
142.5, 143.1, 148.6, 155.7, 171.7 ppm. HRMS (FAB): calcd. for
C21H29N4O4 [M + H]+ 401.2183; found 401.2183.
(2S)-2-(N-Boc-amino)-N-{(1R)-1-[1-allyl-3-(2-furyl)-1H-5-pyr-
azolyl]-2-propenyl}propanamide (14ab): White solid (160 mg, 93%).
[α]2D5 = +142.6 (c = 1.5, CHCl3); m.p. 96–98 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.34 (d, J = 6.9 Hz, 3 H, CH3), 1.39 (s, 9
H, 3 CH3), 4.18 (m, 1 H, CH), 4.70–4.85 (m, 2 H, CH2), 4.95 (d,
J = 7.2 Hz, 1 H, NH), 5.20–5.30 (m, 4 H, 2 CH2), 5.72–5.76 (m, 1
(2S)-2-(N-Boc-amino)-N-[(4R)-2-(2-furyl)-4,7-dihydropyrazolo-
[1,5-a]pyridin-4-yl]propanamide (16ab): White solid (168.1 mg,
1
92%). [α]2D5 = –57.5 (c = 1.0, CHCl3); m.p. 178–180 °C. H NMR
(300 MHz, CDCl3): δ = 1.34 (s, 9 H, 3 CH3), 1.35 (d, J = 6.9 Hz,
3 H, CH3), 4.13–4.18 (m, 1 H, CH), 4.61–4.77 (m, 2 H, CH2), 5.13
(d, J = 7.2 Hz, 1 H, NH), 5.75–5.79 (m, 1 H, CH), 5.85–5.90 (m,
1 H, CHH), 6.02–6.08 (m, 1 H, CHH), 6.38 (s, 1 H, CH), 6.41 (dd,
1
H, CH), 5.90–6.04 (m, 2 H, 2 CH), 6.34 (s, 1 H, CH), 6.42 (dd, J
2
1
2
2
1
2
1J = 3.3, J = 1.8 Hz, 1 H, CH), 6.57 (dd, J = 3.3, J = 0.6 Hz, 1
= 3.3, J = 1.8 Hz, 1 H, CH), 6.58 (dd, J = 3.3, J = 0.6 Hz, 1 H,
CH), 6.81 (br., 1 H, NH), 7.39 (dd, 1J = 1.8, 2J = 0.6 Hz, 1 H,
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 17.6, 28.2, 46.0, 50.0,
52.2, 80.5, 102.3, 105.5, 111.2, 116.7, 117.5, 133.0, 134.4, 141.6,
142.5, 143.1, 148.6, 155.6, 171.7 ppm. HRMS (FAB): calcd. for
C21H29N4O4 [M + H]+ 401.2183; found 401.2197.
1
2
H, CH), 6.96 (br., 1 H, NH), 7.39 (dd, J = 1.8, J = 0.6 Hz, 1 H,
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 17.9, 28.1, 42.0, 46.8,
49.9, 80.3, 100.1, 105.7, 111.1, 123.1, 123.7, 138.6, 141.7, 143.8,
148.6, 155.5, 172.2 ppm. HRMS (FAB): calcd. for C19H25N4O4 [M
+ H]+ 373.1870; found 373.1873.
(2S)-2-(N-Boc-amino)-N-{(1S)-1-[1-allyl-3-(2-furyl)-1H-5-pyr-
azolyl]-3-butenyl}propanamide (15aa): White solid (144.2 mg, 81%).
[α]2D5 = –121.22 (c = 1.1, CHCl3); m.p. 44–46 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.26 (d, J = 6.9 Hz, 3 H, CH3), 1.36 (s, 9
H, 3 CH3), 2.46–2.63 (m, 2 H, CH2), 3.99–4.08 (m, 1 H, CH), 4.76
(d, J = 4.7 Hz, 2 H, CH2), 4.87 (d, J = 5.5 Hz, 1 H, NH), 4.99–
5.15 (m, 5 H, CH2, CH2, CH), 5.63–5.73 (m, 1 H, CH), 5.87–5.98
(2S)-2-(N-Boc-amino)-N-[(4S)-2-(2-furyl)-5,8-dihydro-4H-pyr-
azolo[1,5-a]azepin-4-yl]propanamide (17aa): White solid (87.9 mg,
53% at 96% conversion). [α]2D5 = –68.7 (c = 0.9, CHCl3); m.p. 68–
1
70 °C. H NMR (300 MHz, CDCl3): δ = 1.33 (d, J = 7.0 Hz, 3 H,
1
CH3), 1.39 (s, 9 H, 3 CH3), 2.35–2.55 (m, 2 H, CH2), 4.15 (dq, J
2
= 7.2, J = 7.0 Hz, 1 H, CH), 4.78–4.93 (m, 2 H, CH2), 5.09 (d, J
= 7.2 Hz, 1 H, NH), 5.35 (td, 1J = 8.6, 2J = 5.3 Hz, 1 H, CH),
5.67–5.79 (m, 2 H, CH, CH), 6.32 (s, 1 H, CH), 6.36 (dd, 1J = 3.3,
2J = 1.7 Hz, 1 H, CH), 6.51 (d, J = 3.3 Hz, 1 H, CH), 7.17 (br., 1
H, NH), 7.34 (d, J = 1.7 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 14.6, 18.1, 28.7, 34.3, 44.4, 50.6, 80.9, 101.5, 111.6,
123.8, 128.0, 142.0, 142.5, 145.0, 149.0, 156.2, 172.5 ppm. HRMS
(EI): calcd. for C20H26N4O4 [M]+ 386.1954; found 386.1957.
1
2
(m, 1 H, CH), 6.38 (s, 1 H, CH), 6.39 (dd, J = 3.2, J = 1.7 Hz, 1
H, CH), 6.52 (br., 1 H, NH), 6.57 (d, J = 3.2 Hz, 1 H, CH), 7.37
1
2
(dd, J = 1.7, J = 0.6 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 16.4, 27.2, 37.9, 42.7, 49.0, 51.2, 79.5, 100.1, 104.5,
110.2, 116.4, 117.8, 131.9, 132.2, 140.7, 142.1, 142.6, 147.7, 154.6,
170.8 ppm. HRMS (EI): calcd. for C22H30N4O4 [M]+ 414.2267;
found 414.2269.
(2S)-2-(N-Boc-amino)-N-[(4R)-2-(2-furyl)-5,8-dihydro-4H-pyr-
(2S)-2-(N-Boc-amino)-N-{(1R)-1-[1-allyl-3-(2-furyl)-1H-5-pyr- azolo[1,5-a]azepin-4-il]propanamide (17ab): White solid (69.7 mg,
azolyl]-3-butenyl}propanamide (15ab): Pale-yellow solid (165.5 mg,
42% at 75% conversion). [α]2D5 = +7.2 (c = 0.9, CHCl3); m.p. 110–
112 °C. 1H NMR (300 MHz, CDCl3): δ = 1.32 (d, J = 7.1 Hz, 3
93%). [α]2D5 = +80.6 (c = 0.9, CHCl3); m.p. 44–46 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.26 (d, J = 7.0 Hz, 3 H, CH3), 1.35 (s, 9 H, CH3), 1.41 (s, 9 H, 3 CH3), 2.39–2.61 (m, 2 H, CH2), 4.14 (dq,
2
H, 3 CH3), 2.45–2.63 (m, 2 H, CH2), 4.05 (q, J = 7.0 Hz, 1 H, CH),
1J = 7.2, J = 7.1 Hz, 1 H, CH), 4.79–4.92 (m, 2 H, CH2), 4.93 (d,
1
2
4.70–4.82 (m, 2 H, CH2), 4.85 (d, J = 7.0 Hz, 1 H, NH), 5.00 (dd,
J = 7.3 Hz, 1 H, NH), 5.37 (td, J = 9.0, J = 3.6 Hz, 1 H, CH),
1J = 17.1, J = 1.1 Hz, 1 H, CH), 5.05–5.15 (m, 4 H, CH2, CH2), 5.70–5.81 (m, 2 H, CH, CH), 6.33 (s, 1 H, CH), 6.37 (dd, 1J = 3.1,
2
5.64–5.73 (m, 1 H, CH), 5.86–5.98 (m, 1 H, CH), 6.34 (s, 1 H, CH), 2J = 1.7 Hz, 1 H, CH), 6.52 (d, J = 3.1 Hz, 1 H, CH), 7.10 (br., 1
1
2
2
6.39 (dd, J = 3.2, J = 1.7 Hz, 1 H, CH), 6.56 (d, J = 3.2 Hz, 1
H, CH), 7.34 (dd, 1J = 1.7, J = 0.6 Hz, 1 H, CH) ppm. 13C NMR
1
2
H, CH), 6.63 (br., 1 H, NH), 7.36 (dd, J = 1.7, J = 0.6 Hz, 1 H, (75.5 MHz, CDCl3): δ = 14.6, 17.2, 28.7, 34.4, 44.4, 50.6, 81.1,
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 18.1, 28.6, 39.4, 44.1, 101.5, 105.8, 111.6, 123.6, 128.1, 141.9, 142.4, 144.9, 149.1, 156.5,
8
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Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 17-09-13 19:40:21
Pages: 12
Pyrazolopyridines and -azepines by Ring-Closing Metathesis
172.2 ppm. HRMS (EI): calcd. for C20H26N4O4 [M]+ 386.1954;
found 386.1959.
oled to –78 °C. Ozone was passed through the solution until the
blue color persisted. Then the reaction was stopped and O2 gas
bubbled through the solution to remove excess ozone. Evaporation
of the solvent gave the crude product, which was purified by flash
chromatography (n-hexane/EtOAc, 1:2; 2% HOAc, for 20; n-hex-
ane/EtOAc, 1:1; 2% HOAc, for 21).
Hydrogenation Reaction: A solution of 16 (205 mg, 0.55 mmol) [or
17 (212 mg, 0.55 mmol)] in dry EtOAc (11 mL) and 10% palladium
on carbon (58.4 mg, 0.055 mmol) was stirred under 1 atm of H2
for 18 h at room temp. At this time, the catalyst was filtered off
through a plug of Celite and the filtrate concentrated under
reduced pressure. The crude mixture was purified by flash
chromatography (n-hexane/EtOAc, 1:2, for 18; n-hexane/EtOAc,
2:1, for 19).
(4S)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-4,5,6,7-tetrahydro-
pyrazolo[1,5-a]pyridine-2-carboxylic Acid (20aa): White solid
(96.1 mg, 80%). [α]2D5 = –9.6 (c = 0.9, MeOH); m.p. 148–150 °C.
1H NMR (300 MHz, CD3OD): δ = 1.33 (d, J = 7.2 Hz, 3 H, CH3),
1.44 (s, 9 H, 3 CH3), 1.76–2.27 (m, 4 H, 2 CH2), 4.01–4.24 (m, 3
(2S)-2-(N-Boc-amino)-N-[(4S)-2-(2-furyl)-4,5,6,7-tetrahydropyr-
azolo[1,5-a]pyridin-4-yl]propanamide (18aa): White solid (165 mg,
80%). [α]2D5 = –10.8 (c = 1.0, CHCl3); m.p. 61–63 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.36 (d, J = 5.4 Hz, 3 H, CH3), 1.37 (s, 9
H, 3 CH3), 1.94–2.23 (m, 4 H, 2 CH2), 4.01–4.10 (m, 1 H, CH),
4.14–4.21 (m, 2 H, CH2), 5.12–5.21 (m, 2 H, CH, NH), 6.32 (s, 1
H, CH2, CH), 5.12–5.17 (m, 1 H, CH), 6.59 (s, 1 H, CH) ppm. 13
C
NMR (75.5 MHz, CD3OD): δ = 18.4, 21.9, 28.3, 28.8, 44.7, 49.2,
51.9, 80.7, 107.2, 143.5, 145.3, 157.6, 166.1, 175.7 ppm. HRMS:
calcd. for C16H25N4O5 [M + H]+ 3531819; found 353.1824.
(4R)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-4,5,6,7-tetrahydro-
pyrazolo[1,5-a]pyridine-2-carboxylic acid (20ab): White solid
(84.0 mg, 70%). [α]2D5 = –30.0 (c = 0.9, MeOH); m.p. 136–138 °C.
1H NMR (300 MHz, CD3OD): δ = 1.32 (d, J = 6.9 Hz, 3 H, CH3),
1.44 (s, 9 H, 3 CH3), 1.77–2.23 (m, 4 H, 2 CH2), 4.03–4.23 (m, 3
1
2
1
H, CH), 6.40 (dd, J = 3.3, J = 1.8 Hz, 1 H, CH), 6.56 (dd, J =
3.3, 2J = 0.7 Hz, 1 H, CH), 6.87 (br., 1 H, NH), 7.37 (dd, 1J = 1.8,
2J = 0.7 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
18.2, 20.8, 27.8, 28.2, 43.5, 47.6, 50.2, 80.2, 100.2, 105.5, 111.3,
140.9 ppm. HRMS (EI): calcd. for C19H27N4O4 [M + H]+
375.2027; found 375.2021.
H, CH2, CH), 5.12–5.16 (m, 1 H, CH), 6.66 (s, 1 H, CH) ppm. 13
C
NMR (75.5 MHz, CD3OD): δ = 18.2, 21.9, 28.2, 28.7, 44.7, 49.2,
51.8, 80.7, 107.4, 143.3, 145.3, 157.7, 166.1, 175.6 ppm. HRMS
(FAB): calcd. for C16H25N4O5 [M + H]+ 353.1819; found 353.1809.
(2S)-2-(N-Boc-amino)-N-[(4R)-2-(2-furyl)-4,5,6,7-tetrahydropyr-
azolo[1,5-a]pyridin-4-yl]propanamide (18ab): White solid (123.7 mg,
1
60%). [α]2D5 = –28.8 (c = 0.9, CHCl3); m.p. 188–190 °C. H NMR
(4S)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-5,6,7,8-tetrahydro-
4H-pyrazolo[1,5-a]azepine-2-carboxylic Acid (21aa): White solid
(87.3 mg, 70%). [α]2D5 = –85.7 (c = 0.8, MeOH); m.p. 128–130 °C.
1H NMR (300 MHz, CD3OD): δ = 1.37 (d, J = 7.1 Hz, 3 H, CH3),
1.48 (s, 9 H, 3 CH3), 1.58–2.09 (m, 6 H, 3 CH2), 4.13 (q, J = 7.1 Hz,
(300 MHz, CDCl3): δ = 1.36 (d, J = 6.9 Hz, 3 H, CH3), 1.39 (s, 9
H, 3 CH3), 1.96–2.24 (m, 4 H, 2 CH2), 4.03–4.21 (m, 3 H, CH2,
CH), 5.06 (d, J = 7.2 Hz, 1 H, NH), 5.12–5.22 (m, 1 H, CH), 6.32
1
2
(s, 1 H, CH), 6.41 (dd, J = 3.3, J = 1.6 Hz, 1 H, CH), 6.56 (dd,
1J = 3.3, J = 0.6 Hz, 1 H, CH), 6.87 (br., 1 H, NH), 7.38 (dd, J
2
1
1
2
1 H, CH), 4.22 (dd, J = 14.2, J = 11.1 Hz, 1 H, CHH), 4.51 (dd,
1J = 14.2, 2J = 5.5 Hz, 1 H, CHH), 5.06 (d, J = 10.2 Hz, 1 H, CH),
6.61 (s, 1 H, CH) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 18.4,
28.5, 28.6, 28.8, 34.9, 48.5, 51.8, 54.7, 80.7, 107.8, 142.8, 148.3,
157.7, 165.4, 175.3 ppm. HRMS (EI): calcd. for C17H26N4O5 [M]+
366.1903; found 366.1898.
= 1.6, J = 0.6 Hz, 1 H, CH) ppm. 13C NMR (75.5 MHz, CDCl3):
2
δ = 17.2, 20.4, 27.4, 27.8, 43.0, 47.2, 49.6, 79.9, 99.9, 105.8, 110.7,
140.5, 141.2, 143.0, 148.3, 155.3, 171.7 ppm. HRMS (FAB): calcd.
for C19H27N4O4 [M + H]+ 375.2027; found 375.2032.
(2S)-2-(N-Boc-amino)-N-[(4S)-2-(2-furyl)-5,6,7,8-tetrahydro-4H-pyr-
azolo[1,5-a]azepin-4-yl]propanamide (19aa): White solid (142Ј9 mg,
67%). [α]2D5 = –67.0 (c = 0.8, CHCl3); m.p. 75–77 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.35 (d, J = 6.9 Hz, 3 H, CH3), 1.42 (s, 9
H, 3 CH3), 1.67–1.91 (m, 6 H, 3 CH2), 4.08–4.18 (m, 2 H, CH2),
(4R)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-5,6,7,8-tetrahydro-
4H-pyrazolo[1,5-a]azepine-2-carboxylic Acid (21ab): White solid
(112.3 mg, 90%). [α]2D5 = +46.5 (c = 0.8, MeOH); m.p. 126–128 °C.
1H NMR (300 MHz, CD3OD): δ = 1.34 (d, J = 7.1 Hz, 3 H, CH3),
1.46 (s, 9 H, 3 CH3), 1.60.2.16 (m, 6 H, 3 CH2), 4.13 (q, J = 7.1 Hz,
1
2
4.43 (dq, J = 14.2, J = 6.5 Hz, 1 H, CH), 4.97 (d, J = 6.5 Hz, 1
H, NH), 5.10 (t, J = 8.8 Hz, 1 H, CH), 6.28 (s, 1 H, CH), 6.37 (dd,
1J = 3.2, 2J = 1.8 Hz, 1 H, CH), 6.51 (d, J = 3.2 Hz, 1 H, CH),
6.99 (br., 1 H, CH), 7.35 (d, J = 1.8 Hz, 1 H, CH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 17.3, 20.4, 29.9, 30.6, 31.3, 37.1, 49.8,
56.4, 83.6, 104.4, 108.3, 114.1, 144.5, 144.8, 148.3, 151.7, 158.9,
174.6 ppm. HRMS (EI): calcd. for C20H28N4O4 [M]+ 388.2110;
found 388.2107.
1
2
1 H, CH), 4.23 (dd, J = 14.3, J = 11.2 Hz, 1 H, CHH), 4.51 (dd,
1J = 14.3, J = 5.6 Hz, 1 H, CHH), 5.02 (d, J = 9.9 Hz, 1 H, CH),
2
6.74 (s, 1 H, CH) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 19.3,
29.7, 29.8, 29.9, 36.1, 49.4, 52.9, 55.9, 81.9, 109.6, 143.9, 149.4,
159.0, 166.6, 176.6 ppm. HRMS (FAB): calcd. for C17H27N4O5 [M
+ H]+ 367.1981; found 367.1966.
Addition of Glycine: The same procedure as used for the Addition
of l-Alanine (see above) was used but by using glycine instead of
l-alanine. Flash chromatography was performed by using n-hexane/
EtOAc (1:3) as eluent.
(2S)-2-(N-Boc-amino)-N-[(4R)-2-(2-furyl)-5,6,7,8-tetrahydro-4H-
pyrazolo[1,5-a]azepin-4-yl]propanamide (19ab): White solid
(138.7 mg, 65%). [α]2D5 = +14.5 (c = 1.0, CHCl3); m.p. 195–197 °C.
1H NMR (300 MHz, CDCl3): δ = 1.32 (d, J = 6.0 Hz, 3 H, CH3),
1.41 (s, 9 H, 3 CH3), 1.62–1.93 (m, 6 H, 3 CH2), 4.07–4.17 (m, 2
(4S)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-2-(ethoxycarbonyl-
methylcarbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (9aa):
White solid (70 mg, 80%). [α]2D5 = –19.9 (c = 1.0, CH3OH); m.p.
1
2
H, CH2), 4.41 (dq, J = 14.5, J = 6.0 Hz, 1 H, CH), 4.98 (d, J =
7.4 Hz, 1 H, NH), 5.08 (t, J = 9.4 Hz, 1 H, CH), 6.28 (s, 1 H, CH),
1
2
6.36 (dd, J = 3.2, J = 1.4 Hz, 1 H, CH), 6.50 (d, J = 3.2 Hz, 1
1
73–75 °C. H NMR (300 MHz, CD3CN): δ = 1.22 (t, J = 7.2 Hz,
1
2
H, CH), 7.03 (br., 1 H, NH), 7.33 (dd, J = 1.4, J = 0.6 Hz, 1 H,
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 17.4, 27.4, 27.9, 28.7,
31.3, 34.5, 47.3, 53.8, 81.1, 101.8, 105.6, 111.5, 141.9, 142.1, 145.7,
149.2, 156.5, 171.9 ppm. HRMS (EI): calcd. for C20H28N4O4 [M]+
388.2110; found 388.2114.
3 H, CH3), 1.27 (d, J = 7.2 Hz, 3 H, CH3), 1.38 (s, 9 H, 3 CH3),
1.68–2.20 (m, 4 H, 2 CH2), 3.97–4.12 (m, 3 H, CH2, CH), 4.01 (dd,
2
1J = 6.1, J = 1.2 Hz, 2 H, CH2), 4.14 (q, J = 7.2 Hz, 2 H, CH2),
5.04–5.12 (m, 1 H, CH), 5.66 (br., 1 H, NH), 6.46 (d, J = 0.9 Hz,
1 H, CH), 7.12 (d, J = 8.4 Hz, 1 H, NH), 7.48 (t, J = 6.1 Hz, 1 H,
NH) ppm. 13C NMR (75.5 MHz, CD3CN): δ = 14.4, 18.4, 21.5,
27.8, 28.5, 41.5, 44.1, 48.8, 51.4, 61.9, 80.0, 104.3, 143.6, 145.8,
Oxidation of the Furyl Ring:
A solution of 18 (127.5 mg,
0.34 mmol) [or 19 (132 mg, 0.34 mmol)] in MeOH (33 mL) was co-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

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/KAP1
Date: 17-09-13 19:40:21
Pages: 12
S. Fustero, A. Simón-Fuentes et al.
FULL PAPER
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P. A. Harris, J. G. Badiang, G. E. Peckham, S. D. Chamberlain,
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Epperly, S. A. Stimpson, M. R. Peel, Bioorg. Med. Chem. Lett.
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156.4, 163.2, 170.9, 173.8 ppm. HRMS (FAB): calcd. for
C20H31N5O6 [M + H]+ 438.2347; found 438.2346.
(4R)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-2-(ethoxycarbonyl-
methylcarbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (9ab):
White solid (60.4 mg, 69%). [α]2D5 = +7.3 (c = 1.0, CH3OH); m.p.
[3]
[4]
a) N. Tschammer, J. Elsner, A. Gotees, K. Ehrlich, S. Schuster,
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1
79–81 °C. H NMR (300 MHz, CD3CN): δ = 1.23 (t, J = 7.0 Hz,
3 H, CH3), 1.27 (d, J = 7.2 Hz, 3 H, CH3), 1.39 (s, 9 H, 3 CH3),
1.60–2.17 (m, 4 H, 2 CH2), 3.96–4.12 (m, 3 H, CH2, CH), 4.02 (dd,
2
1J = 6.0, J = 2.7 Hz, 2 H, CH2), 4.15 (q, J = 7.0 Hz, 2 H, CH2),
5.05–5.12 (m, 1 H, CH), 5.65 (br., 1 H, NH), 6.49 (d, J = 0.9 Hz,
1 H, CH), 7.05 (d, J = 8.4 Hz, 1 H, NH), 7.42 (t, J = 6.0 Hz, 1 H,
NH) ppm. 13C NMR (75.5 MHz, CD3CN): δ = 14.4, 18.2, 21.4,
27.9, 28.5, 41.4, 44.1, 48.8, 51.3, 61.8, 79.8, 104.5, 143.5, 145.9,
156.4, 162.9, 171.0, 173.4 ppm. HRMS (FAB): calcd. for
C20H31N5O6 [M + H]+ 438.2347; found 438.2347.
(4S)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-2-(ethoxycarbonyl-
methylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine
(10aa): White solid (76.6 mg, 85%). [α]2D5 = –53.8 (c = 1.1, CHCl3);
m.p. 104–106 °C. 1H NMR (300 MHz, CDCl3): δ = 1.28, (t, J =
7.1 Hz, 3 H, CH3), 1.37 (d, J = 6.9 Hz, 3 H, CH3), 1.45 (s, 9 H, 3
CH3), 1.61–2.03 (m, 6 H, 3 CH2), 4.15–4.20 (m, 4 H, CH2, CH,
[5]
[6]
1
2
CHH), 4.22 (q, J = 6.9 Hz, 2 H, CH2), 4.44 (dd, J = 14.3, J =
1
5.2 Hz, 1 H, CHH), 5.04 (d, J = 7.0 Hz, 1 H, NH), 5.12 (dd, J =
9.5, 2J = 9.3 Hz, 1 H, CH), 6.62 (s, 1 H, CH), 7.15 (br., 1 H, NH),
7.26 (t, J = 5.6 Hz, 1 H, NH) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 14.1, 14.2, 17.8, 27.1, 27.4, 28.3, 34.1, 41.0, 46.9, 50.1, 53.8,
61.4, 80.3, 104.8, 143.6, 146.3, 162.1, 169.9, 171.3 ppm. HRMS
(EI): calcd. for C21H33N5O6 [M]+ 451.2431; found 451.2434.
[7]
[8]
(4R)-4-[(2S)-2-(N-Boc-amino)propanoylamino]-2-(ethoxycarbonyl-
methylcarbamoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine
(10ab): White solid (74.8 mg, 83%). [α]2D5 = +36.5 (c = 1.0, MeOH);
m.p. 105–107 °C. 1H NMR (300 MHz, CD2Cl2): δ = 1.41 (t, J =
7.1 Hz, 3 H, CH3), 1.54 (d, J = 7.2 Hz, 3 H, CH3), 1.57 (s, 9 H, 3
CH3), 1.76–2.27 (m, 6 H, 3 CH2), 4.25 (d, J = 5.8 Hz, 2 H, CH2),
4.31–4.38 (m, 2 H, CHH, CH), 4.34 (q, J = 7.1 Hz, 2 H, CH2),
[9]
[10]
[11]
[12]
1
2
4.57 (dd, J = 14.5, J = 5.8 Hz, 1 H, CHH), 5.16–5.25 (m, 2 H,
CH, NH), 6.61 (s, 1 H, CH), 7.09 (br., 1 H, NH), 7.39 (t, J =
4.8 Hz, 1 H, NH) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 14.5,
18.4, 28.4, 28.7, 28.8, 34.9, 41.9, 51.8, 54.8, 62.3, 80.8, 106.0, 144.6,
148.0, 157.5, 164.9, 171.4, 175.2 ppm. HRMS (EI): calcd. for
C21H33N5O6 [M]+ 451.2431; found 451.2430.
[13]
[14]
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8, 3426–3436.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new compounds, crystallo-
graphic data for compounds 9aa and 15aa.
Acknowledgments
The authors would like to thank the Spanish Ministerio de Ciencia
e Innovación (MICINN) (CTQ2010-19774) and the Generalitat
Valenciana (PROMETEO/2010/061) for their financial support.
[15]
[16]
X. H. Jiang, L. D. Song, Y. Q. Long, J. Org. Chem. 2003, 68,
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Peckham, J. M. Veal, M. Cheung, P. A. Harris, S. D. Chamber-
When RCM was performed with the Grubbs’ second-genera-
tion catalyst, in the presence of p-toluensulfonic acid (Y. Chen,
10
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Job/Unit: O30901
/KAP1
Date: 17-09-13 19:40:21
Pages: 12
Pyrazolopyridines and -azepines by Ring-Closing Metathesis
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[25] When allylzinc bromide was used instead of allylmagnesium
bromide, the yield was similar (82%) but the selectivity lower
(13aa/13ab = 1:2.5).
[27]
[28]
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[29] Suitable crystals were obtained by slow evaporation of a solu-
tion of (S,S)-15aa in DCM/hexane at room temperature.
CCDC-941485 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[30] Suitable crystals were obtained by slow evaporation of a solu-
tion of (S,S)-9aa in DCM/hexane at room temperature;
CCDC-841484.
Received: June 20, 2013
[26] X.-W. Sun, M. Liu, M.-H. Xu, G.-Q. Lin, Org. Lett. 2008, 10,
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Published Online: ᭿
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Job/Unit: O30901
/KAP1
Date: 17-09-13 19:40:21
Pages: 12
S. Fustero, A. Simón-Fuentes et al.
FULL PAPER
Heterocyclic Chemistry
S. Fustero,* R. Román, A. Asensio,
M. A. Maestro, J. L. Aceña,
A. Simón-Fuentes* .......................... 1–12
An Approach to 2,4-Substituted Pyr-
azolo[1,5-a]pyridines and Pyrazolo[1,5-a]-
azepines by Ring-Closing Metathesis
Keywords: Synthetic methods / Asymmetric
synthesis / Metathesis / Peptidomimetics /
Nitrogen heterocycles
The N-allylation of readily available 3,5-
substituted pyrazoles followed by ring-clos-
ing metathesis of the resulting 1,5-diolef-
inic derivatives leads to the formation of
and pyrazolo[1,5-a]azepines in high yields.
The application of this protocol to the dia-
stereoselective synthesis of potential pepti-
domimetics is described.
2,4-substituted
pyrazolo[1,5-a]pyridines
12
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