Application of Pd-Catalyzed Cross-Coupling Reactions in the Synthesis of 5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles that Inhibit ALK5 Kinase

Article abstract of DOI:10.1021/acs.joc.6b02230

C-H activation of position 3 of a substituted pyrazole ring catalyzed by palladium(II) was straightforward and convenient for arylated or heteroarylated 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. Moreover, we introduced simple protection of the nitrogen in the pyridin-2-yl directing group, which otherwise does not allow a cross-coupling reaction, by transformation to the N-oxide. Selected final products were reasonably selective ALK5 kinase inhibitors.

Full text of DOI:10.1021/acs.joc.6b02230

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Article
Application of Pd-Catalyzed Cross-Coupling Reactions in the Synthesis of
,5-Dimethyl-5,6-dihydro-4-#-pyrrolo[1,2-b]pyrazoles that inhibit ALK5 Kinase
5
Lukas Tenora, Juraj Galeta, Eva #ezní#ková, Vladimir Krystof, and Milan Potacek
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02230 • Publication Date (Web): 24 Oct 2016
Downloaded from http://pubs.acs.org on October 28, 2016
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Application of Pd-Catalyzed Cross-Coupling Reactions in the Synthesis of 5,5-Dimethyl-
5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles that inhibit ALK5 Kinase
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a
a,†
b
b
a,
Lukáš Tenora, Juraj Galeta, Eva Řezníčková, Vladimír Kryštof, Milan Potáček *
a
Department of Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37
Brno, Czech Republic
b
Laboratory of Growth Regulators, Faculty of Science, Palacký University & Institute of
Experimental Botany ASCR, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
ABSTRACT: C-H activation of position 3 of a substituted pyrazole ring catalyzed by
palladium(II) was straightforward and convenient for arylated or heteroarylated 5,5-
dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. Moreover, we introduced simple
protection of the nitrogen in the pyridin-2-yl directing group, which otherwise does not
allow cross-coupling reaction, by transformation to the N-oxide. Selected final products
were reasonably selective ALK5 kinase inhibitors.
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Introduction
The development of new synthetic strategies for molecular construction by organic
chemists has always been challenging and the improved production of complex
molecules from simple, nontoxic and economically available starting materials is always
desirable. In today’s chemistry, the cross-coupling reaction is among the most employed
strategies of every synthetic lab and C–H activation/functionalization process appears to
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be a wonderful synthetic tool for molecular derivatizations. The main disadvantage of
this method compared to classical cross-coupling reactions is a requisite directing group
at the appropriate position, which is often unwanted in the final product. The solution is
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the direct functionalization of a C–H bond which is an ever-growing area of interest.
The atom economy and fast accessibility of the desired and often biologically active
products make these reactions really attractive.
In the past, we developed a convenient synthetic protocol for molecules containing a
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,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (DPP) core containing various
substituents via protected hydrazone 1 formation / homoallenyl azine 2 generation /
thermal intramolecular cycloaddition reaction cascade leading to DPP 3 heterocycles
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(Experimental Section). This structural motif appears in several compounds with
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attractive biological activities, e.g. plant alkaloid withasomnine , synthetic β3 adrenergic
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receptor agonists and kinase inhibitors, including galunisertib (LY2157299), a drug that
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is currently under clinical investigation in cancer patients (Figure 1). Galunisertib has
been developed as an inhibitor of transforming growth factor-β (TGF-β) type I receptor
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f-i,6
kinase (TGFBR1, also known as ALK5).
Binding of TGF-β to this transmembrane
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receptor enables its kinase activity leading to highly complex intracellular signalling
pathway regulating proliferation, differentiation, migration, extracellular matrix
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production and apoptosis. Due to known deregulation of TGF-β signalling in several
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diseases, ALK5 and other components of the pathway have been studied as possible
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drug targets for different therapeutic uses.
These findings and a longstanding interest in the preparation of DPPs in our laboratory
led us to investigate the reactivity of such a core more thoroughly as means to find
biologically active products. Thus, we applied various Pd-catalyzed transformations on
synthesized derivatives 3a-e (Experimental Section) facilitating fast accessibility of
structurally enriched products.
Figure 1. Synthesized DPPs 3a-e as a starting material and two examples of bioactive
compounds containing the respective core
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Results and Discussion
We divided the study into two parts depending on the position of nitrogen atom bound
to the side aromatic substituent at C2, the pyridin-2-yl and pyridin-4-yl moieties. We
explored the reactivity of latter DPPs first (Scheme 1) and applied this chemistry further
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to pyridin-2-yl derivatives, which are known to be biologically more potent. We
synthesized chloro, bromo and iodo compounds 4a-c and then applied Heck (5a-d),
Sonogashira (5e-j) and Suzuki (5k-r) cross-coupling reaction protocols. In general, all
reactions we carried out afforded good to high yields. However, direct arylation clearly
showed feasibility only for electron-deficient aryl bromides whereas electron-rich
counterparts revealed negligible conversions (Scheme 1). Using the data resulting from
preliminary biological testing we selected the most promising compounds and prepared
relevant structures bearing quinolin-4-yl (3b) and 2-cyanophenyl (3c) substitutions at C2
(Experimental Section).
Scheme 1. Transformations at C3 on derivative 3a
Halogenations (X)
Heck cross-coupling products (Y)
Sonogashira cross-coupling products (Y)
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Suzuki cross-coupling products (Y)
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j
Direct arylations (conversions)
a) NCS, anh. CHCl , rt, 18 h; b) NBS, anh. CHCl , rt, 0.5 h; c) NIS, anh. CHCl /MeCN, rt to 60 °C, 23 h; d) 4b,
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substituted alkene, Pd(dba) , P(t-Bu) , Et N, DMF, 100 °C, 2-8 h; e) 1 M DIBAL-H/DCM, 0 °C, 1 h; f) 4c,
2
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substituted acetylene, Pd(PPh ) Cl , Et N, CuI, MeCN, 70 °C, 1 h; g) K CO , MeOH, rt, 0.5 h; h) aryl iodide,
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Pd(PPh ) Cl , Et N, CuI, MeCN, 70 °C, 1 h; i) 4b, arylboronic acid, Pd(PPh ) , 2 M aq. K CO , DMF, 110 °C, 1
3
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3 4
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h; j) followed by NMR; k) ArBr, Pd(OAc) , KOAc, DMA, 150 °C, 25 h (up to 100 h for 5k-m); l) 81% yield; m)
2
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0% yield
We then applied this established reactivity of 2-(pyridin-4-yl)-DPPs (Scheme 1) to
pyridin-2-yl derivatives. Initial screening of the arylation reactions at C3 on a DPP core
bearing pyridin-2-yl moiety at C2 started with halogenation at C3 and subsequent cross-
coupling. Unfortunately, we observed no reaction whatsoever. We assume that the
steric strain between the nitrogen lone electron pair and the bulk bromine atom causes
repulsion in 6b, which leads to the preferred orientation after rotation around the σ
bond. This arrangement appears similar to known bidentate ligands such as 2,2’-
bipyridyl or 1,10-phenanthroline interacting in the presence of palladium catalyst as
shown at Figure 2 (A – B resonance). And, in fact, such a highly electron-deficient
pyrazole core with a reinforced bond between bromine and the carbon atom is unable
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to undergo oxidative addition and, thus, any palladium-catalyzed transformation (Figure
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Figure 2. Plausible explanation of the unreactivity of 6b toward Pd-catalyzed cross-
coupling reactions (P = phosphine ligand)
To avoid this complication we protected the pyridine nitrogen atom by transformation
to the N-oxide (9c, 9d) and, fortunately, such compounds easily afforded the desired
Suzuki cross-coupling products in reasonable yields. We chose two examples and
obtained products 7d/8b over two steps (Suzuki and N-oxide deprotection) in 64 and
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4% yield, respectively, and products 7l/8e in 53 and 55% yield, respectively (not
shown). This simple procedure might be applicable to a much more complex systems
and, to our knowledge, has never been applied previously. In fact, there is precedence
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in the literature where reactions between simple aromatic N-oxides and olefins led to
ortho substituted aromatic N-oxides. But the authors clearly demonstrated that without
oxidant the reaction did not proceed. In our case Suzuki cross coupling reaction is
superior to the ortho substitution of pyridin-2-yl N-oxide moiety in intermediate 9c and
besides the intermediate 9d is fully occupied at ortho positions. However, in our case,
the best candidate for such a transformation is a C-H activation/functionalization
sequence where we observed consistently good yields over the reaction course. The
only exceptions were the potentially sterically hindered derivative 7g and reactive
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chloropyridyl analog 8j, which provided lower yields. Likewise, derivative 7q with simple
phenyl substitution presented decreased reactivity in line with the transition from
electron-deficient to electron-neutral aromatic substituents. One important highlight
worth mentioning is the formation of products 7r/8l bearing donor substituent. These
substrates demonstrate a clear unwillingness to undergo direct C-H activation (we
observed only negligible conversions), although N-oxide pathway afforded the desired
products in high yields (Scheme 2).
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Scheme 2. Transformations at C3 on derivatives 3d and 3e
Halogenations (X)
C-H activation / functionalization (Ar)
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Oxidation and bromination
a) NCS, anh. CHCl , rt, 16 h; b) NBS, anh. CHCl , rt, 0.5 h (6b), 0.75 h (6d), 1 h (9c,d); c) NIS, anh. MeCN, rt,
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.5 h; d) 3d or 3e, aryl halide, Pd(OAc) , KOAc, DMA, 150 °C, 20 – 100 h; e) 7a, Pd/C, H , anh. MeOH, rt, 4
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h; f) 7d, NaBH , anh. MeOH, rt, 0.5 h; g) 7j or 8c, 1M NaOH, EtOH/THF, rt, 16 h or 18 h; h) 7o or 8h, K CO ,
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Na S O , H O /H O, DMSO, rt, 3–4 h; i) 8j, sulfanilamide, Cs CO , Pd(OAc) , Xantphos, anh. DMF, 150 °C, 1
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h; j) 9c or 9d, arylboronic acid, Pd(PPh ) , JohnPhos, 2 M aq. K CO , DMF, 110 °C, 16–25 h, then HCOONH ,
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Pd/C, anh. MeOH, reflux, 1–2 h; k) 1 M BBr , anh. DCM, -78 °C to rt, 20 h; l) MCPBA, anh. DCM, 0 °C to rt,
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20 h
Optimization of reaction conditions is shown in the SI. Among others, we tried to avoid
the use of high boiling solvents, however the best one was DMA followed by DMF. We
also tested several strong non-nucleophilic bases including phosphazene P1, Verkade’s
proazaphosphatrane and DBU but without success. Carbonates and phosphates did not
work either but KOAc turned out to be the best choice. It worked with a range of
palladium catalysts but the combination of palladium acetate/potassium acetate was
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revealed to be superior. We attempted the C-H activation in the presence of ligand first
but we later determined that the reaction proceeded smoothly even without it.
With this knowledge in hand, we were able to propose a reaction mechanism (Figure 3).
We assume that in the first step the catalyst coordinates to pyridyl moiety and interacts
with a single C-H bond (P). Then upon acetic acid departure intermediate Q is formed
which is in equilibrium with nonreactive palladacycle R. Molecule Q then undergoes
oxidative addition with the respective aryl halide and such a reactive palladium(IV)
complex S rapidly decomposes and releases desired products 7 after reductive
elimination. Finally, the catalytic cycle would end with regeneration of catalyst.
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Figure 3. Proposed general catalytic cycle for C-H activation
Due to the known interaction of 2,3-disubstituted DPP in the TGF-β signalling
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d,6g-i
pathway,
all the compounds were tested in a kinase assay using purified human
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ALK5 kinase domain (SI). The assay revealed that the compounds are specific for ALK5
(over ABL and CDK2) and the structure-activity relationships of novel DPPs are similar to
5d,6g-i
those of related known ALK5 inhibitors.
Briefly, also our new active compounds
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bear either a pyridin-2-yl (7l, 7s) or 6-methylpyridin-2-yl (8e-g, 8i, 8k, 8m) ring at
position C2. Position C3 should be occupied by pyridin-4-yl (7l, 8e), 4-hydroxyphenyl (7s,
8m) or quinolin-4-yl (8g, 8i) moieties. Further derivatization of the pyridin-4-yl ring at
position C3 led to the formation of sulfanilamide 8k, one of the most potent inhibitor
within this series (Figure 4). Data for the less potent products are summarized in the SI.
Another important finding from our biochemical study was that position C5 of DPP
tolerates two methyl groups, indicating that the corresponding part of the ALK5’s
binding pocket may be flexible enough to accommodate substitution at this position.
This has been demonstrated with a 5,5-dimethyl homologue of galunisertib (compound
8
i) that also showed activity towards ALK5 (IC value of 0.6 µM). This position of the
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DPP scaffolding has not been previously explored and therefore we chose to prepare
novel derivatives and study the impact of this modification on biochemical activity.
Interestingly, quinolyn-4-yl derivatives (7n-p, 8g-i) inhibited also tyrosine kinase ABL,
suggesting that bulkier C3 substitution may significantly alter the compounds‘ selectivity
(see SI). These findings proved that our short synthesis employing non-symmetrical
homoallenyl azines is a very efficient way to prepare the aforementioned biologically
active compounds. In addition, apparent broader kinase selectivity of some new
derivatives may stimulate further studies leading possibly to novel kinase inhibitors.
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Figure 4. Examples of prepared compounds displaying ALK5 inhibition. Numbers indicate
IC values.
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Conclusions
In summary, we describe a straightforward synthesis of novel 5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazoles leading to a small library of 57 final products. In the final stage
of the synthesis, we exploit Heck, Sonogashira and Suzuki cross-coupling reactions as
well as C-H activation and direct arylation methods. We propose a general catalytic cycle
to rationalize the C-H activation reaction. Also, we introduce useful protection of
pyridin-2-yl nitrogen atom as the N-oxide, which facilitated the synthesis of otherwise
inaccessible products. Moreover, all synthesized DPP derivatives exhibited reasonable
potency and selectivity towards ALK5 kinase and may serve as a starting point for
further optimization as kinase inhibitors with possible pharmacological applications.
Experimental Section
General Information. Unless otherwise noted, all reagents were purchased from
commercial suppliers and used as received. All reactions were carried out under a dry
argon atmosphere. Toluene and xylene were distilled from sodium turnings and stored
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over active 3 Å molecular sieves. Melting points were determined in open capillaries.
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NMR spectra were recorded at 400 MHz ( H) and 100 MHz ( C) with CDCl , CD OD,
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CD ) SO or CD CN as solvents. Data are presented as follows: chemical shift (in ppm),
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multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, sept =
septet, m = multiplet), coupling constant (J/Hz) and integration. Internal standards (in
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ppm) for H and C NMR spectra were δ 7.26 and 77.23 for CDCl , δ 3.31 and 49.00 for
3
CD OD, δ 2.50 and 39.52 for (CD ) SO and δ 1.94 and 1.32 for CD CN. Particular signals
3
3 2
3
1
13
in H and C NMR spectra were assigned using 2D NMR experiments (HSQC, HMBC). IR
spectra of neat compounds or KBr tablets were measured on an FT-IR spectrometer.
High-resolution mass spectra (HRMS) were recorded in the positive ESI mode on a LTQ
Orbitrap XL, for some azines CI or EI ionization were used. Elemental analyses were
performed with a CHN apparatus. Some compounds were purified by preparative HPLC.
The analysis was performed using a gradient of 2% B to 70% B over 60 min on a C18, 250
×
20 mm column at a flow rate 10 ml/min, where A: 0.1% TFA/water and B: acetonitrile
210 nm). Column chromatography was performed on Silica gel 60 and thin-layer
chromatography (TLC) on Silica gel 60 F254 foils. The diffraction data were collected using
diffraction system equipped with rotating anode X-ray source (λ = 0.71075 Å), partial
axis goniometer, CCD detector and a cooling device. Structure solution and refinement
(
χ
9
,10
was performed using SHELX software.
General Scheme for DPPs 3 preparation and numbering used for NMR characterization
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General Procedure for the Preparation of Protected Hydrazones 1a-e. To a solution of
diethyl hydrazinylphosphonate (7.85 g, 46.7 mmol) in DCM (75 mL) a solution of
appropriate aldehyde (46.7 mmol) in DCM (40 mL) in few portions was added
(exothermic reaction). The reaction mixture was refluxed using Dean-Stark condenser
until the consumption of starting material (1.5 h) and purified.
Diethyl N´-pyridin-4-ylmethylenephosphorohydrazidate (1a). Column chromatography
1
(
MeOH/DCM 1:20) afforded 12.0 g, >99% of colorless oil. H NMR (400 MHz, CDCl ): δ
3
H
2
3
3
9.10 (d, J = 29.3, 1H, NH), 8.61 (d, J = 5.9, 2H, 2×CH), 7.83 (s, 1H, CH), 7.48 (d, J =
P,H
3
13
1
5
.9, 2H, 2×CH), 4.12–4.31 (m, 4H, CH CH ), 1.38 (t, J = 7.1, 6H, CH CH ). C { H} NMR
2 3 2 3
3
(100 MHz, CDCl ): δ 150.2 (2×CH), 142.3 (C), 142.2 (d, J = 19.6, CH), 120.8 (2×CH),
3
C
P,C
2
3
6
3.9 (d, J = 5.8, CH CH ), 16.3 (d, J = 6.8, CH CH ). FTIR (neat): 3422, 3129, 2983,
P,C 2 3 P,C 2 3
2931, 2910, 2818, 1595, 1548, 1477, 1445, 1408, 1394, 1369, 1234, 1164, 1101, 1018.
+
HRMS (ESI) m/z: [M + H] Calcd. for C H N O P: 258.1002. Found: 258.1002.
1
0 17 3 3
Diethyl
N´-quinolin-4-ylmethylenephosphorohydrazidate
(1b).
Column
chromatography (MeOH/EtOAc 1:8) afforded 13.9 g, 97% of light yellow solid; mp
1
2
3
112.7–113.8 °C. H NMR (400 MHz, CDCl ): δ 9.37 (d, J = 29.2, 1H, NH), 8.93 (d, J =
3
H
P,H
4
.5, 1H, CH), 8.54–8.60 (m, 1H, CH), 8.54 (s, 1H, CH), 8.12–8.18 (m, 1H, CH), 7.70–7.78
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(
m, 1H, CH), 7.68 (d, J = 4.5, 1H, CH), 7.55–7.64 (m, 1H, CH), 4.19–4.39 (m, 4H, CH CH ),
2 3
3
13
1
1.42 (t, J = 7.0, 6H, CH CH ). C { H} NMR (100 MHz, CDCl ): δ 150.2 (CH), 149.1 (C),
2
3
3
C
3
1
41.7 (d, J = 20.0, CH), 138.1 (C), 130.4 (CH), 129.5 (CH), 127.3 (CH), 125.4 (C), 124.2
P,C
0
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2
3
4
5
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8
9
0
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
6
7
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0
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5
6
7
8
9
0
2
3
(CH), 119.2 (CH), 63.9 (d, J = 5.8, CH CH ), 16.4 (d, J = 6.8, CH CH ). FTIR (neat):
P,C
2
3
P,C
2
3
3
130, 2959, 2908, 2865, 1607, 1569, 1513, 1391, 1235, 1204, 1171, 1113, 1023. HRMS
+
(ESI) m/z: [M + H] Calcd. for C H N O P: 308.1159. Found: 308.1159.
1
4 19 3 3
Diethyl N´-(2-cyanophenyl-1-yl)methylenephosphorohydrazidate (1c). Column
1
chromatography (EtOAc) afforded 12.5 g, 95% of yellowish solid; mp 117.8–119.0 °C. H
2
3
NMR (400 MHz, CDCl ): δ 8.50 (d, J = 28.9, 1H, NH), 8.18 (s, 1H, CH), 7.99 (d, J = 8.0,
3
H
P,H
3
3
3
1H, CH), 7.64 (d, J = 7.6, 1H, CH), 7.57 (t, J = 7.7, 1H, CH), 7.40 (t, J = 7.6, 1H, CH),
3
13
1
4
.13–4.30 (m, 4H, CH CH ), 1.37 (t, J = 7.0, 6H, CH CH ). C { H} NMR (100 MHz, CDCl ):
2 3 2 3 3
3
δ 140.5 (d, J = 19.6, CH), 137.4 (C), 133.1 (CH), 132.9 (CH), 129.3 (CH), 126.3 (CH),
C
P,C
2
3
1
17.3 (CH), 110.9 (CN), 63.8 (d, JP,C = 5.6, CH CH ), 16.3 (d, J = 6.9, CH CH ). FTIR
2 3 P,C 2 3
(
neat): 3323, 3139, 3002, 2941, 2932, 2910, 2227, 1608, 1590, 1565, 1470, 1442, 1394,
+
1
371, 1296, 1243, 1165, 1119, 1028, 982. HRMS (ESI) m/z: [M + H] Calcd. for
C H N O P: 282.1002. Found: 282.1003.
1
2 17 3 3
Diethyl N´-pyridin-2-ylmethylenephosphorohydrazidate (1d). Column chromatography
1
(
MeOH/DCM 1:20) afforded 12.0 g, >99% of colorless oil. H NMR (400 MHz, CDCl ): δ
3
H
2
8
.71 (d, J = 28.8, 1H, NH), 8.54–8.60 (m, 1H, CH), 8.01 (s, 1H, CH), 7.87–7.95 (m, 1H,
P,H
3
CH), 7.62–7.71 (m, 1H, CH), 7.17–7.25 (m, 1H, CH), 4.10–4.32 (m, 4H, CH CH ), 1.37 (t, J
2
3
1
3
1
=
7.1, 6H, CH CH ). C { H} NMR (100 MHz, CDCl ): δ 153.9 (C), 149.3 (CH), 145.6 (d,
2 3 3 C
3
2
JP,C = 19.0, CH), 136.4 (CH), 123.5 (CH), 120.1 (CH), 63.5 (d, JP,C = 5.5, CH CH ), 16.3 (d,
2
3
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9
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JP,C = 6.8, CH CH ). FTIR (neat): 3469, 3056, 2983, 2929, 2909, 2855, 1594, 1556, 1474,
2
3
+
1445, 1411, 1392, 1293, 1244, 1164, 1100, 1018. HRMS (ESI) m/z: [M + Na] Calcd. for
C H N O NaP: 280.0822. Found: 280.0822.
1
0 16 3 3
10
11
12
13
14
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17
18
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Diethyl N´-(6-methylpyridin-2-yl)methylenephosphorohydrazidate (1e). Column
1
chromatography (EtOAc/DCM 1:20) afforded 12.5 g, >99% of colorless oil. H NMR (400
2
3
MHz, CDCl ): δ 8.09 (d, J = 28.6, 1H, NH), 7.88 (s, 1H, CH), 7.70 (d, J = 7.8, 1H, CH),
3
H
P,H
3
3
7
.55 (t, J = 7.7, 1H, CH), 7.06 (d, J = 7.5, 1H, CH), 4.02–4.29 (m, 4H, CH CH ), 2.52 (s, 3H,
2 3
3
13
1
CH -Ar), 1.34 (t, J = 7.0, 6H, CH CH ). C { H} NMR (100 MHz, CDCl ): δ 158.0 (C), 153.1
3
2
3
3
C
3
2
(
C), 145.8 (d, J = 18.6, CH), 136.6 (CH), 123.2 (CH), 117.2 (CH), 63.6 (d, JP,C = 5.5,
P,C
3
CH CH ), 24.4 (CH -Ar), 16.3 (d, J = 6.9, CH CH ). FTIR (neat): 3325, 3141, 3067, 2995,
2
3
3
P,C
2
3
2
1
2
942, 2932, 2910, 2870, 1603, 1589, 1573, 1479, 1452, 1443, 1395, 1377, 1370, 1320,
+
292, 1243, 1156, 1106, 980. HRMS (ESI) m/z: [M + H] Calcd. for C H N O P:
1
1 19 3 3
72.1159. Found: 272.1159.
General Procedure for the Preparation of Nonsymmetrical Homoallenyl Azines 2a-e.
To an anhydrous toluene (50 mL) was added NaH (636 mg, 26.5 mmol, 1.5 equiv.) and
the mixture was cooled down to 0 °C. To this suspension a solution of 2,2-
1
2
dimethylpenta-3,4-dienal (1.96 g, 17.7 mmol) and protected hydrazone 1a-e (19.4
mmol, 1.1 equiv.) in anhydrous toluene (20 mL) was added dropwise over a period of 15
min. The temperature was kept within 0–5 °C range. The reaction mixture was left to
heat up to rt. When the starting material disappeared on TLC (1-2 h), the mixture was
filtered and the solid residue was washed with Et O and DCM (3×10 mL each). Solvent
2
was evaporated and products were purified.
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-(((2,2-Dimethylpenta-3,4-dienylidene)hydrazono)methyl)pyridine (2a).
Column
1
chromatography (EtOAc) afforded 3.13 g, 83% of light yellow liquid. H NMR (400 MHz,
3
3
CDCl ): δ 8.70 (d, J = 4.7, 2H, 2×CH), 8.38 (s, 1H, CH), 7.85 (s, 1H, CH), 7.61 (d, J = 4.7,
3
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0
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4
2H, 2×CH), 5.28 (t, J = 6.6, 1H, HC=C=CH ), 4.86 (d, J = 6.6, 2H, =CH ), 1.32 (s, 6H, H C-
2
2
3
13
1
C-CH ). C { H} NMR (100 MHz, CDCl ): δ 207.2 (=C=), 171.1 (HC=N), 158.3 (HC=N),
3
3
C
150.6 (2×CH), 141.2 (C), 122.0 (2×CH), 97.2 (=CH ), 78.0 (HC=C), 38.4 (H C-C-CH ), 25.6
2
3
3
(H C-C-CH ). FTIR (neat): 2969, 2930, 2886, 2868, 1954, 1646, 1594, 1552, 1463, 1444,
3 3
+
1408, 1384, 1363, 1310, 1233, 1195, 1147, 990. HRMS (EI) m/z: [M] Calcd. for C H N :
1
3 15 3
2
13.1266. Found: 213.1263.
4-(((2,2-Dimethylpenta-3,4-dienylidene)hydrazono)methyl)quinoline (2b). Column
1
chromatography (EtOAc) afforded 3.64 g, 78% of yellow liquid. H NMR (400 MHz,
3
3
3
CDCl ): δ 9.07 (s, 1H, CH), 8.99 (d, J = 4.5, 1H, CH), 8.66 (d, J = 8.4, 1H, CH), 8.18 (d, J =
3
H
3
8
.4, 1H, CH), 7.98 (s, 1H, CH), 7.80 (d, J = 4.5, 1H, CH), 7.72–7.79 (m, 1H, CH), 7.59–7.66
4
4
(m, 1H, CH), 5.33 (t, J = 6.7, 1H, HC=C=CH ), 4.88 (d, J = 6.7, 2H, =CH ), 1.36 (s, 6H, H C-
2 2 3
1
3
1
C-CH ). C { H} NMR (100 MHz, CDCl ): δ 207.3 (=C=), 171.6 (HC=N), 158.1 (HC=N),
3
3
C
1
1
3
1
50.3 (CH), 149.2 (C), 137.5 (C), 130.5 (CH), 129.8 (CH), 127.8 (CH), 125.9 (C), 124.4 (CH),
20.8 (CH), 97.3 (=CH ), 78.1 (HC=C), 38.5 (H C-C-CH ), 25.7 (H C-C-CH ). FTIR (neat):
2
3
3
3
3
058, 3034, 2968, 2929, 2885, 2867, 1954, 1704, 1646, 1610, 1581, 1562, 1506, 1462,
+
424, 1385, 1361, 1323, 1302, 1250, 1211, 1161, 1137, 1088. HRMS (ESI) m/z: [M + H]
Calcd. for C H N : 264.1495. Found: 264.1496.
1
7 18 3
3
-(((2,2-Dimethylpenta-3,4-dien-1-ylidene)hydrazono)methyl)benzonitrile
(2c).
Column chromatography (EtOAc/hexane 1:8) afforded 3.23 g, 77% of light yellow liquid.
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H NMR (400 MHz, CDCl ): δ 8.79 (s, 1H, CH), 8.18 (d, J = 7.9, 1H, CH), 7.87 (s, 1H, CH),
3
H
3
3
3
4
7.74 (d, J = 7.6, 1H, CH), 7.66 (t, J = 7.4, 1H, CH), 7.54 (t, J = 7.6, 1H, CH), 5.26 (t, J =
4
13
1
6
.7, 1H, HC=C=CH ), 4.84 (d, J = 6.7, 2H, =CH ), 1.27 (s, 6H, H C-C-CH ). C { H} NMR
2 2 3 3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(100 MHz, CDCl ): δ 207.1 (=C=), 168.7 (HC=N), 156.3 (HC=N), 136.6 (C), 133.4 (CH),
3
C
1
33.0 (CH), 131.0 (CH), 127.5 (CH), 117.0 (C), 113.0 (CN), 97.3 (=CH ), 77.8 (HC=C), 38.1
2
(H C-C-CH ), 25.6 (H C-C-CH ). FTIR (neat): 3059, 2969, 2929, 2887, 2868, 2224, 1955,
3
3
3
3
1
700, 1647, 1627, 1593, 1465, 1384, 1363, 1309, 1288, 1222, 1194, 1147, 1090, 1018,
+
991. HRMS (CI) m/z: [M + H] Calcd. for C H N : 238.1344. Found: 238.1346.
1
5 16 3
2
-(((2,2-Dimethylpenta-3,4-dienylidene)hydrazono)methyl)pyridine (2d). Column
1
chromatography (EtOAc) afforded 3.47 g, 92% of light yellow liquid. H NMR (400 MHz,
CDCl ): δ 8.65–8.69 (m, 1H, CH), 8.47 (s, 1H, CH), 7.96–8.01 (m, 1H, CH), 7.85 (s, 1H,
3
H
4
CH), 7.69–7.77 (m, 1H, CH), 7.27–7.33 (m, 1H, CH), 5.30 (t, J = 6.7, 1H, HC=C=CH ), 4.85
2
4
13
1
(
d, J = 6.7, 2H, =CH ), 1.32 (s, 6H, H C-C-CH ). C { H} NMR (100 MHz, CDCl ): δ 207.1
2 3 3 3 C
(=C=), 170.0 (HC=N), 160.2 (HC=N), 153.1 (C), 149.9 (CH), 136.5 (CH), 124.8 (CH), 122.0
(
CH), 97.2 (=CH ), 77.8 (HC=C), 38.2 (H C-C-CH ), 25.5 (H C-C-CH ). FTIR (neat): 3056,
2
3
3
3
3
2
968, 2929, 2886, 2867, 1954, 1646, 1630, 1586, 1567, 1465, 1436, 1384, 1363, 1309,
+
1
218, 1194, 1148, 1090, 1044, 992. HRMS (EI) m/z: [M] Calcd. for C H N : 213.1266.
1
3 15 3
Found: 213.1262.
2
-(((2,2-Dimethylpenta-3,4-dienylidene)hydrazono)methyl)-6-methylpyridine
(2e).
Column chromatography (EtOAc/hexane 1:4) afforded 3.50 g, 87% of light yellow liquid.
1
3
H NMR (400 MHz, CDCl ): δ 8.38 (s, 1H, CH), 7.78 (s, 1H, CH), 7.72 (d, J = 7.7, 1H, CH),
3
H
3
3
4
7
.59 (t, J = 7.7, 1H, CH), 7.14 (d, J = 7.7, 1H, CH), 5.25 (t, J = 6.7, 1H, HC=C=CH ), 4.80
2
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1
(
d, J = 6.7, 2H, =CH ), 2.56 (s, 3H, CH -Ar), 1.27 (s, 6H, H C-C-CH ). C { H} NMR (100
2 3 3 3
MHz, CDCl ): δ 207.1 (=C=), 169.6 (HC=N), 160.2 (HC=N), 158.7 (C), 152.4 (C), 136.7
3
C
(
CH), 124.6 (CH), 119.4 (CH), 97.2 (=CH ), 77.8 (HC=C), 38.2 (H C-C-CH ), 25.5 (H C-C-
2 3 3 3
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH ), 24.5 (CH -Ar). FTIR (neat): 3058, 2966, 2926, 2855, 1955, 1699, 1647, 1630, 1587,
3
3
1
568, 1456, 1384, 1372, 1363, 1301, 1249, 1237, 1221, 1145, 1083, 1039, 986, 958.
+
HRMS (CI) m/z: [M + H] Calcd. for C H N : 228.1501. Found: 228.1502.
1
4 18 3
General Procedure for the Preparation of Starting DPPs 3a-e. 3.00 g of nonsymmetrical
homoallenyl azine 2a-e was dissolved in anhydrous xylene (25 mL, mixture of isomers)
and refluxed under an argon atmosphere (8 h for 3a,d; 9 h for 3b; 4 h for 3c; 7 h for 3d).
Solvent was evaporated and the crude product was purified by column chromatography
(
EtOAc for 3a,b,d and EtOAc/hexane 1:3 for 3c,e).
5
9
1
,5-Dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (3a). Yield 2.76 g,
1
3
2% of yellow-orange solid; mp 109.5–109.8 °C. H NMR (CDCl ): δ 8.59 (dd, J = 4.6,
3
H
3
.6, 2H, 2×CH), 7.64 (dd, J = 4.6, 1.6, 2H, 2×CH), 6.36 (s, 1H, H3), 3.94 (s, 2H, H6), 2.73
1
3
1
(
s, 2H, H4), 1.32 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 152.9 (C), 150.4 (C), 146.8
3 C
(
2×CH), 141.7 (C), 119.8 (2×CH), 97.7 (C3), 61.4 (C6), 43.3 (C5), 39.0 (C4), 28.3 (C5a,b).
FTIR (neat): 3034, 2965, 2932, 2873, 1601, 1557, 1536, 1514, 1467, 1435, 1419, 1366,
1
315, 1219, 1202, 1172, 988. Anal. Calcd. for C H N : C, 73.21; H, 7.09; N, 19.70.
13 15 3
Found: C, 72.89; H, 7.03; N, 19.90.
4
9
8
-(5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)quinoline (3b). Yield 2.76 g,
1
3
3
2% of yellow oil. H NMR (CDCl ): δ 8.91 (d, J = 4.5, 1H, CH), 8.74 (d, J = 8.5, 1H, CH),
3
H
3
3
3
3
.14 (d, J = 8.4, 1H, CH), 7.71 (t, J = 7.6, 1H, CH), 7.58 (d, J = 4.4, 1H, CH), 7.54 (t, J =
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.2, 1H, CH), 6.37 (s, 1H, H3), 4.01 (s, 2H, H6), 2.78 (s, 2H, H4), 1.35 (s, 6H, H5a,b). C
1
{ H} NMR (CDCl ): δ 152.8 (C), 150.2 (CH), 149.2 (C), 146.1 (C), 140.4 (C), 129.9 (CH),
3
C
1
29.3 (CH), 126.8 (CH), 126.7 (CH), 126.2 (C), 120.5 (CH), 100.9 (C3), 61.5 (C6), 43.3 (C5),
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11
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
39.0 (C4), 28.4 (C5a,b). FTIR (neat): 3042, 2957, 2870, 1583, 1565, 1541, 1511, 1467,
1
439, 1419, 1381, 1370, 1353, 1318, 1284, 1268, 1215, 1177, 1024. HRMS (ESI) m/z: [M
+
+ H] Calcd. for C H N : 264.1495. Found: 264.1492.
1
7 17 3
2
-(5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)benzonitrile (3c). Yield 2.46
1
g, 82% of light yellow solid; mp 83.2–84.3 °C. H NMR (CDCl ): δ 7.93–7.97 (m, 1H, CH),
3
H
7
.66–7.70 (m, 1H, CH), 7.54–7.60 (m, 1H, CH), 7.31–7.36 (m, 1H, CH), 6.68 (s, 1H, H3),
1
3
1
3.94 (s, 2H, H6), 2.74 (s, 2H, H4), 1.31 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 151.8 (C),
3
C
1
9
2
1
46.5 (C), 137.6 (C), 134.0 (CH), 132.8 (CH), 128.3 (CH), 127.4 (CH), 119.5 (C), 109.2 (CN),
9.5 (C3), 61.3 (C6), 43.2 (C5), 38.9 (C4), 28.3 (C5a,b). FTIR (neat): 2965, 2931, 2882,
873, 2860, 2226, 1600, 1540, 1504, 1486, 1464, 1452, 1441, 1415, 1390, 1372, 1354,
326, 1301, 1287, 1272, 1252, 1231, 1200, 1174, 1164, 1105, 1069, 1035, 967. HRMS
+
(
ESI) m/z: [M + H] Calcd. for C H N : 238.1339. Found: 238.1339.
1
5 16 3
5
8
,5-Dimethyl-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (3d). Yield 2.64 g,
1
8% of light yellow-orange solid; mp 92.4–93.2 °C. H NMR (CDCl ): δ 8.58–8.62 (m, 1H,
3
H
CH), 7.87–7.91 (m, 1H, CH), 7.64–7.71 (m, 1H, CH), 7.13–7.18 (m, 1H, CH), 6.60 (s, 1H,
1
3
1
H3), 3.94 (s, 2H, H6), 2.74 (s, 2H, H4), 1.32 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 155.8
3
C
(
C), 153.1 (C), 149.5 (CH), 146.4 (C), 136.5 (CH), 122.2 (CH), 119.8 (CH), 98.2 (C3), 61.3
C6), 43.3 (C5), 39.0 (C4), 28.3 (C5a,b). FTIR (neat): 3044, 3006, 2960, 2931, 2868, 1587,
(
1
563, 1499, 1473, 1451, 1409, 1387, 1370, 1362, 1316, 1271, 1201, 1143, 1126, 1088,
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2
2
2
2
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3
3
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4
4
4
4
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5
5
5
5
5
5
5
5
5
6
1
060, 1041, 991. Anal. Calcd. for C H N : C, 73.21; H, 7.09; N, 19.70. Found: C, 73.09;
1
3 15 3
H, 7.17; N, 19.88.
5
,5-Dimethyl-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
(3e).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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6
7
8
9
0
1
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Yield 2.58 g, 86% of light yellow solid; mp 101.6–102.8 °C. H NMR (CDCl ): δ 7.62 (d, J
3
H
3
3
=
7.8, 1H, CH), 7.56 (t, J = 7.7, 1H, CH), 7.03 (d, J = 7.5, 1H, CH), 6.56 (s, 1H, H3), 3.94 (s,
1
3
1
2H, H6), 2.72 (s, 2H, H4), 2.59 (s, 3H, CH -Ar), 1.30 (s, 6H, H5a,b). C { H} NMR (CDCl ):
3
3
δC 158.1 (C), 155.8 (C), 152.3 (C), 146.1 (C), 136.6 (CH), 121.6 (CH), 116.8 (CH), 98.1 (C3),
61.1 (C6), 43.2 (C5), 38.8 (C4), 28.1 (C5a,b), 24.7 (CH -Ar). FTIR (neat): 2959, 2924, 2876,
3
2
867, 1591, 1573, 1544, 1496, 1453, 1429, 1407, 1386, 1369, 1348, 1322, 1268, 1199,
+
1171, 1154, 1128, 1091, 1073, 1007, 991. HRMS (ESI) m/z: [M + H] Calcd. for C H N :
1
4 17 3
2
28.1495. Found: 228.1497.
Alternative Method: 3d (1.00 g, 4.69 mmol) was dissolved in anhydrous Et O (50 mL) and
2
the solution was cooled down to -70 °C under an argon atmosphere. A 1.6 M solution of
methyl lithium (7.3 mL, 11.7 mmol, 2.5 equiv.) was added dropwise. The red mixture
was stirred for 0.5 h at the same temperature and then heated up to rt and stirred for 1
h. The reaction was quenched with sat. NH Cl (12 mL) and water (10 mL). Water phase
4
was extracted with DCM (2×25 mL), combined organic phases were dried over Na SO ,
2
4
filtered and evaporated. The crude product was purified by column chromatography
EtOAc/DCM 1:1) to yield 362 mg (34%) of desired product.
(
Pyridin-4-yl, Quinolin-4-yl and 2-Cyanophenyl Substituted Products at C2:
Halogenations.
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-Chloro-5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (4a). 3a
(1.00 g, 4.69 mmol) was dissolved in anhydrous CHCl (40 mL) and NCS (2.50 g, 18.8
3
mmol, 4 equiv.) was added in few portions. The reaction mixture was stirred for 18
hours at rt under an argon atmosphere. The mixture was washed with 10% aq. Na SO
10
11
12
13
14
15
16
17
18
19
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54
55
56
57
58
59
60
2
4
(
25 mL) and then with water (3×25 mL). The organic layer was dried over Na SO ,
2 4
filtered and evaporated. Column chromatography (EtOAc) afforded 1.05 g, 91% of light
1
3
yellow solid; mp 54.2–55.0 °C. H NMR (CDCl ): δ 8.61 (dd, J = 4.6, 1.6, 2H, 2×CH), 7.84
3
H
3
13
1
(dd, J = 4.6, 1.6, 2H, 2×CH), 3.92 (s, 2H, H6), 2.72 (s, 2H, H4), 1.31 (s, 6H, H5a,b). C { H}
NMR (CDCl ): δ 149.8 (2×CH), 147.4 (C), 144.3 (C), 140.4 (C), 121.0 (2×CH), 103.1 (C3),
3
C
62.3 (C6), 43.2 (C5), 38.1 (C4), 28.3 (C5a,b). FTIR (neat): 2959, 2933, 2905, 2870, 2853,
1
599, 1558, 1464, 1434, 1416, 1360, 1333, 1262, 1219, 1024, 989. HRMS (ESI) m/z: [M +
+
H] Calcd. for C H N Cl: 248.0949. Found: 248.0952.
1
3 14 3
3
-Bromo-5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (4b). 3a
(1.00 g, 4.69 mmol) was dissolved in anhydrous CHCl (20 mL) and NBS (0.96 g, 5.39
3
mmol, 1.15 equiv.) was added in few portions. The reaction mixture was stirred for 1 h
at rt under an argon atmosphere. DCM (20 mL) was added and the mixture was washed
with 10% aq. Na S O (10 mL) and water (3×20 mL). The organic layer was dried over
2
2 5
Na SO , filtered and evaporated. Column chromatography (EtOAc/DCM 1:1) afforded
2
4
1
3
1
=
6
.28 g, 93% of light yellow-orange solid; mp 73.3–74.0 °C. H NMR (CDCl ): δ 8.64 (d, J
3 H
3
6.0, 2H, 2×CH), 7.86 (d, J = 6.0, 2H, 2×CH), 3.98 (s, 2H, H6), 2.73 (s, 2H, H4), 1.35 (s,
1
3
1
H, H5a,b). C { H} NMR (CDCl ): δ 150.0 (2×CH), 148.9 (C), 146.5 (C), 140.5 (C), 121.2
3
C
(2×CH), 86.6 (C3), 62.4 (C6), 42.9 (C5), 38.4 (C4), 28.3 (C5a,b). FTIR (neat): 3035, 2968,
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951, 2932, 2902, 2877, 2848, 1597, 1556, 1539, 1465, 1449, 1428, 1414, 1390, 1371,
1354, 1322, 1255, 1219, 1173, 1008, 990. Anal. Calcd. for C H N Br: C, 53.44; H, 4.83;
1
3 14 3
N, 14.38. Found: C, 53.77; H, 4.85; N, 14.20.
3-Iodo-5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (4c). 3a
1.00 g, 4.69 mmol) was dissolved in a mixture of anhydrous MeCN (25 mL) and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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7
8
9
0
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4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
(
anhydrous CHCl (15 mL). NIS (3.16 g, 14.1 mmol, 3 equiv.) was added in few portions.
3
The reaction mixture was stirred for 0.5 h at rt and then refluxed for 17 h under an
argon atmosphere. Solvents were evaporated and the residue was dissolved in DCM (30
mL), washed with 10% aq. Na S O (30 mL) and water (3×30 mL). Combined water
2
2 5
phases were extracted with DCM (10 mL). Organic layers were dried over Na SO and
2
4
solvent was evaporated. Column chromatography (EtOAc) afforded 1.29 g, 81% of an
1
3
off-white solid; mp 119.8–120.0 °C. H NMR (CDCl ): δ 8.65 (dd, J = 4.6, 1.6, 2H, 2×CH),
3
H
3
13
7
.84 (dd, J = 4.6, 1.6, 2H, 2×CH), 4.02 (s, 2H, H6), 2.71 (s, 2H, H4), 1.34 (s, 6H, H5a,b). C
1
{
(
H} NMR (CDCl ): δ 152.0 (C), 150.9 (C), 150.1 (2×CH), 141.1 (C), 121.7 (2×CH), 62.6
3
C
C6), 50.2 (C3), 42.6 (C5), 39.2 (C4), 28.4 (C5a,b). FTIR (neat): 3080, 3030, 2961, 2939,
2
1
4
4
906, 2871, 2851, 1601, 1550, 1524, 1483, 1438, 1424, 1412, 1373, 1352, 1320, 1263,
229, 1213, 1175, 1156, 1106, 1064, 1002, 992. Anal. Calcd. for C H N I: C, 46.03; H,
1
3 14 3
.16; N, 12.39. Found: C, 46.18; H, 4.20; N, 12.26.
-(3-Bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)quinoline
(4d).
Follow the same procedure as for product 4b, reaction time was 1.5 h. 3b (1.0 g, 3.80
mmol) and N-bromosuccinimide (811 mg, 4.56 mmol, 1.2 equiv.) afforded after column
chromatography (EtOAc/DCM 1:1) 1.16 g, 89% of light yellow-orange solid; mp 115.4–
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16.7 °C. H NMR (400 MHz, CDCl ): δ 8.98 (d, J = 4.4, 1H, CH), 8.23 (d, J = 8.3, 1H,
3
H
3
3
3
CH), 8.17 (d, J = 8.4, 1H, CH), 7.72 (t, J = 7.2, 1H, CH), 7.57 (d, J = 4.4, 1H, CH), 7.54 (t,
3
13
1
J = 7.3, 1H, CH), 4.04 (s, 2H, H6), 2.78 (s, 2H, H4), 1.37 (s, 6H, H5a,b). C { H} NMR (100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl ): δ 150.1 (C), 149.8 (CH), 148.9 (C), 145.8 (C), 138.6 (C), 129.8 (CH), 129.5
3
C
(CH), 126.9 (CH), 126.8 (CH), 126.7 (C), 122.3 (CH), 88.4 (C3), 62.6 (C6), 43.1 (C5), 38.6
(C4), 28.4 (C5a,b). FTIR (neat): 2958, 2928, 2868, 1586, 1565, 1544, 1514, 1471, 1450,
1
370, 1349, 1311, 1286, 1266, 1175, 1139, 1119, 1046. Anal. Calcd. For C H N Br: C,
17 16 3
59.66; H, 4.71; N, 12.28. Found: C, 59.57; H, 4.75; N, 12.09.
2
-(3-Bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)benzonitrile (4e).
Follow the same procedure as for product 4b, reaction time was 1.5 h. 3c (1.00 g, 4.21
mmol) and N-bromosuccinimide (1.13 g, 6.32 mmol, 1.5 equiv.) afforded after column
chromatography (EtOAc/hexane 1:4) 1.27 g, 95% of light yellow solid; mp 118.1–119.6
1
°
C. H NMR (400 MHz, CDCl ): δ 7.75–7.79 (m, 1H, CH), 7.69–7.72 (m, 1H, CH), 7.61–
3
H
7
.66 (m, 1H, CH), 7.44–7.49 (m, 1H, CH), 4.01 (s, 2H, H6), 2.75 (s, 2H, H4), 1.36 (s, 6H,
1
3
1
H5a,b). C { H} NMR (100 MHz, CDCl ): δ 149.9 (C), 145.7 (C), 135.9 (C), 133.8 (CH),
3
C
1
3
2
1
32.3 (CH), 130.6 (CH), 128.5 (CH), 118.5 (C), 112.4 (CN), 87.4 (C3), 62.4 (C6), 42.9 (C5),
8.5 (C4), 28.4 (C5a,b). FTIR (neat): 3072, 2986, 2976, 2961, 2927, 2904, 2881, 2871,
226, 1597, 1541, 1486, 1463, 1455, 1449, 1433, 1417, 1400, 1390, 1373, 1349, 1339,
316, 1300, 1288, 1277, 1266, 1257, 1176, 1162, 1111, 1088, 1040, 1028, 1004, 984.
+
HRMS (ESI) m/z: [M + H] Calcd. for C H N Br: 316.0444. Found: 316.0446.
1
5 15 3
Pyridin-4-yl Substituted Products at C2: Heck Cross-Coupling and Related Products. 4b
(
100 mg, 0.342 mmol) and Pd(dba) (9.8 mg, 5 mol% for 5a,b and 20 mg, 10 mol% for 5c)
2
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were dissolved in anhydrous DMF (2 mL). Et N (95 µL, 2 equiv.), P(t-Bu) (8 µL, 10 mol%
3
3
for 5a,b and 13 µL, 15 mol% for 5c) and relevant alkene - 4-methoxystyrene (91 µL, 2
equiv. for 5a), 4-methylstyrene (68 µL, 1.5 equiv. for 5b) or methyl acrylate (155 µL, 5
equiv. for 5c) were added. The mixture was stirred at 100 °C under an argon atmosphere
for 2 h (5a), 8 h (5b) or 4 h (5c). DMF was evaporated and the crude product was
purified by column chromatography (EtOAc). Both cis and trans isomers formed in 5a
and 5b were separated during the purification.
0
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2
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0
3-(4-Methoxystyryl)-5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazole (5a). Yield 107 mg, 90%; cis/trans 35:65, cis - yellow oil, trans - a colorless
1
3
solid; mp 121.0–121.9 °C. cis isomer: H NMR (CDCl ): δ 8.43 (d, J = 6.1, 2H, 2×CH),
3
H
3
3
3
7
.52 (d, J = 6.1, 2H, 2×CH), 7.29 (d, J = 8.8, 2H, 2×CH), 6.78 (d, J = 8.8, 2H, 2×CH), 5.56
3
3
(
d, J = 1.2, 1H, CH), 5.11 (d, J = 1.2, 1H, CH), 3.97 (s, 2H, H6), 3.77 (s, 3H, OCH ), 2.53 (s,
3
1
3
1
2
1
H, H4), 1.30 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 159.7 (C), 150.5 (C), 149.8 (2×CH),
3 C
46.4 (C), 141.8 (C), 140.1 (CH), 132.8 (C), 128.1 (2×CH), 121.9 (2×CH), 115.0 (C3), 114.2
(
CH), 113.9 (2×CH), 61.6 (C6), 55.4 (OCH ), 43.2 (C5), 38.7 (C4), 28.3 (C5a,b). trans
3
1
3
3
isomer: H NMR (CDCl ): δ 8.65 (d, J = 5.7, 2H, 2×CH), 7.59 (d, J = 5.7, 2H, 2×CH), 7.35
3
H
3
3
3
3
(
d, J = 8.6, 2H, 2×CH), 6.94 (d, J = 16.3, 1H, CH), 6.87 (d, J = 8.6, 2H, 2×CH), 6.62 (d, J =
1
6.3, 1H, CH), 3.94 (s, 2H, H6), 3.79 (s, 3H, OCH ), 2.91 (s, 2H, H4), 1.36 (s, 6H, H5a,b).
3
1
3
1
C { H} NMR (CDCl ): δ 159.1 (C), 150.7 (C), 150.0 (2×CH), 143.7 (C), 141.8 (C), 130.4
3
C
(C), 128.0 (CH), 127.1 (2×CH), 122.4 (2×CH), 117.2 (CH), 114.2 (2×CH), 112.6 (C3), 61.2
(
C6), 55.3 (OCH ), 43.2 (C5), 39.9 (C4), 28.4 (C5a,b). FTIR (neat, cis): 3034, 2958, 2930,
3
2
872, 2838, 1642, 1600, 1574, 1509, 1462, 1437, 1415, 1389, 1370, 1323, 1305, 1293,
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248, 1173, 1162, 1112, 1065, 1029, 992; trans: 3035, 2961, 2930, 2905, 2874, 2836,
1597, 1509, 1487, 1464, 1435, 1417, 1370, 1320, 1305, 1292, 1274, 1250, 1219, 1173,
+
1
116, 1035, 991. HRMS (ESI) m/z: [M + H] Calcd. for C H N O: 346.1914. Found:
2
2 23 3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
33
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56
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60
346.1909.
5
,5-Dimethyl-3-(4-methylstyryl)-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
(5b). Yield 106 mg, 94%; cis/trans 28:72, cis - yellow oil, trans - a colorless solid; mp
1
3
3
1
18.5–118.6 °C. cis isomer: H NMR (CDCl ): δ 8.42 (d, J = 6.1, 2H, 2×CH), 7.52 (d, J =
3 H
3
3
3
6.1, 2H, 2×CH), 7.26 (d, J = 8.1, 2H, 2×CH), 7.06 (d, J = 8.1, 2H, 2×CH), 5.62 (d, J = 1.2,
3
1
H, CH), 5.16 (d, J = 1.2, 1H, CH), 3.97 (s, 2H, H6), 2.51 (s, 2H, H4), 2.31 (s, 3H, Ph-CH ),
3
1
3
1
1.30 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 150.5 (C), 149.8 (2×CH), 146.3 (C), 141.8 (C),
3
C
1
1
40.6 (CH), 138.0 (C), 137.3 (C), 129.2 (2×CH), 126.8 (2×CH), 121.9 (2×CH), 115.1 (CH),
1
14.9 (C3), 61.6 (C6), 43.2 (C5), 38.7 (C4), 28.3 (C5a,b), 21.3 (Ph-CH ). trans isomer: H
3
3
3
3
NMR (CDCl ): δ 8.65 (d, J = 5.8, 2H, 2×CH), 7.58 (d, J = 5.8, 2H, 2×CH), 7.31 (d, J = 8.0,
3
H
3
3
3
2
H, 2×CH), 7.13 (d, J = 8.0, 2H, 2×CH), 7.03 (d, J = 16.3, 1H, CH), 6.64 (d, J = 16.3, 1H,
1
3
1
CH), 3.94 (s, 2H, H6), 2.91 (s, 2H, H4), 2.33 (s, 3H, Ph-CH ), 1.36 (s, 6H, H5a,b). C { H}
3
NMR (CDCl ): δ 150.9 (C), 150.1 (2×CH), 144.0 (C), 141.9 (C), 137.2 (C), 134.9 (C), 129.5
3
C
(2×CH), 128.5 (CH), 125.9 (2×CH), 122.5 (2×CH), 118.3 (CH), 112.6 (C3), 61.3 (C6), 43.2
(C5), 40.0 (C4), 28.5 (C5a,b), 21.3 (Ph-CH ). FTIR (neat, cis): 3083, 3028, 2958, 2926,
3
2
1
1
872, 1648, 1602, 1539, 1510, 1488, 1464, 1438, 1415, 1389, 1370, 1324, 1267, 1216,
179, 1117, 1066, 1041, 992; trans: 3026, 2957, 2928, 2866, 1602, 1537, 1513, 1490,
+
462, 1438, 1415, 1370, 1328, 1274, 1216, 1183, 1170. HRMS (ESI) m/z: [M + H] Calcd.
for C H N : 330.1965. Found: 330.1964.
2
2 23 3
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Methyl-3-(5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-
yl)acrylate (5c). Yield 89 mg, 87%; cis/trans 5:95, trans - a colorless solid; mp 127.8–
1
3
3
1
28.4 °C. H NMR (CDCl ): δ 8.69 (d, J = 4.9, 2H, 2×CH), 7.72 (d, J = 15.9, 1H, CH), 7.51
3 H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
(d, J = 4.9, 2H, 2×CH), 6.01 (d, J = 15.9, 1H, CH), 3.98 (s, 2H, H6), 3.77 (s, 3H, OCH ), 2.90
3
13
1
(
s, 2H, H4), 1.38 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 167.5 (C=O), 153.0 (C), 150.2
3 C
(2×CH), 146.4 (CH), 140.7 (C), 135.5 (2×CH), 122.7 (C), 116.2 (CH), 110.0 (C3), 61.3 (C6),
1.5 (OCH ), 43.3 (C5), 40.0 (C4), 28.4 (C5a,b). FTIR (neat): 2963, 2940, 2909, 2887,
5
3
2871, 2832, 1701, 1632, 1600, 1557, 1534, 1489, 1437, 1428, 1418, 1326, 1308, 1287,
+
1
266, 1233, 1193, 1068, 1020, 989. HRMS (ESI) m/z: [M + H] Calcd. for C H N O :
1
7 19 3 2
298.1550. Found: 298.1546. CCDC 1497729
3
1
-(5,5-Dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)prop-2-en-
-ol (5d). 5c (100 mg, 0.336 mmol) was dissolved in anhydrous DCM (4 mL). The reaction
mixture was cooled down to 0 °C and 1 M DIBAL-H in DCM (1.0 mL, 3 equiv.) was added
dropwise within 10 min. The colorless mixture was stirred at 0 °C for 1 h and then the
reaction was quenched with 1 M HCl (to pH 7). Water was added (10 mL) and the
product was extracted with DCM (3×7 mL). Combined organic phases were washed with
brine (15 mL), dried over Na SO4 and evaporated. Column chromatography
2
1
(
MeOH/DCM 1:15) afforded 70 mg, 77% of a colorless solid; mp 153.7–154.8 °C. H NMR
3
3
3
(
CDCl ): δ 8.50 (d, J = 4.8, 2H, 2×CH), 7.47 (d, J = 4.8, 2H, 2×CH), 6.54 (d, J = 15.9, 1H,
3
H
3
3
CH), 5.92 (dt, J = 15.9, 5.7, 1H, CH), 4.23 (d, J = 5.7, 2H, CH OH), 3.87 (s, 2H, H6), 3.72
2
1
3
1
(
bs, 1H, OH), 2.76 (s, 2H, H4), 1.28 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 150.3 (C),
3 C
1
49.7 (2×CH), 144.4 (CH), 142.1 (C), 129.3 (C), 122.5 (2×CH), 121.1 (CH), 111.8 (C3), 63.5
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(
CH OH), 61.2 (C6), 43.2 (C5), 39.7 (C4), 28.4 (C5a,b). FTIR (neat): 3245, 3052, 3015,
2
2968, 2953, 2923, 2896, 2871, 2849, 1606, 1538, 1436, 1418, 1372, 1347, 1323, 1296,
+
1
273, 1212, 1183, 1126, 1088, 1064, 1002. HRMS (ESI) m/z: [M + H] Calcd. for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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57
58
59
60
C H N O: 270.1601. Found: 270.1603.
1
6 20 3
Pyridin-4-yl Substituted Products at C2: Sonogashira Cross-Coupling and Related
Products. 4c (100 mg, 0.295 mmol), relevant acetylene (2 equiv. for 5e,f and 6 equiv. for
5
g), CuI (10 mol%), Pd(PPh ) Cl (5 mol%) and Et N (3 equiv.) were dissolved in
3 2 2 3
anhydrous MeCN (2.5 mL). The mixture was stirred at 70 °C under an argon atmosphere
for 1 h. MeCN was evaporated and the crude products were purified and finally
crystallized from MeCN.
3
-((4-Methoxyphenyl)ethynyl)-5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-
pyrrolo[1,2-b]pyrazole (5e). Column chromatography (EtOAc/DCM 2:1) afforded 80 mg,
1
8
7
0% of yellow solid; mp 127.2–127.5 °C. H NMR (CDCl ): δ 7.75–8.70 (m, 4H, 4×CH),
3
H
3
3
.44 (d, J = 8.7, 2H, 2×CH), 6.88 (d, J = 8.7, 2H, 2×CH), 3.92 (s, 2H, H6), 3.80 (s, 3H,
1
3
1
OCH ), 2.84 (s, 2H, H4), 1.32 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 159.7 (C), 152.2 (C),
3
3
C
1
9
49.8 (2×CH), 149.6 (C), 140.5 (C), 132.7 (2×CH), 120.5 (2×CH), 115.6 (C), 114.2 (2×CH),
6.3 (-C≡C-), 93.3 (-C≡C-), 80.1 (C3), 61.8 (C6), 55.4 (OCH ), 43.1 (C5), 38.7 (C4), 28.2
3
(C5a,b). FTIR (neat): 3027, 2958, 2940, 2906, 2869, 2849, 2838, 2220, 1600, 1565, 1504,
1
462, 1437, 1420, 1374, 1367, 1326, 1283, 1246, 1177, 1165, 1106, 1019, 991. HRMS
+
(
ESI) m/z: [M + H] Calcd. for C H N O: 344.1757. Found: 344.1754.
2
2 21 3
5
,5-Dimethyl-3-(phenylethynyl)-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
(
5f). Column chromatography (EtOAc) afforded 81 mg, 88% of yellow solid; mp 116.0–
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4
4
4
4
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5
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5
5
5
5
5
5
6
1
1
16.9 °C. H NMR (CDCl ): δ 7.85–8.55 (m, 4H, 4×CH), 7.44–7.52 (m, 2H, 2×CH), 7.28–
3 H
1
3
1
7.36 (m, 3H, 3×CH), 3.89 (s, 2H, H6), 2.82 (s, 2H, H4), 1.30 (s, 6H, H5a,b). C { H} NMR
(
CDCl ): δ 152.4 (C), 150.0 (2×CH), 149.9 (C), 140.8 (C), 131.3 (2×CH), 128.5 (2×CH),
3
C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
128.3 (CH), 123.5 (C), 120.3 (2×CH), 96.0 (-C≡C-), 93.5 (-C≡C-), 81.6 (C3), 61.8 (C6), 43.1
C5), 38.7 (C4), 28.3 (C5a,b). FTIR (neat): 3071, 3023, 2955, 2923, 2877, 2849, 2219,
(
1596, 1569, 1540, 1486, 1466, 1448, 1435, 1418, 1372, 1312, 1301, 1264, 1250, 1225,
+
1
3
5
174, 1158, 1066, 989. HRMS (ESI) m/z: [M + H] Calcd. for C H N : 314.1657. Found:
2
1 19 3
14.1647. CCDC 1497730
,5-Dimethyl-2-(pyridin-4-yl)-3-((trimethylsilyl)ethynyl)-5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazole (5g). Column chromatography (EtOAc/DCM 1:1) afforded 458 mg, 95% of a
1
colorless solid; mp 132.9–133.1 °C. H NMR (CDCl ): δ 8.64 (bs, 2H, 2×CH), 8.00 (bs, 2H,
3
H
1
3
1
2
×CH), 3.82 (s, 2H, H6), 2.73 (s, 2H, H4), 1.22 (s, 6H, H5a,b), 0.20 (s, 9H, TMS). C { H}
NMR (CDCl ): δ 152.5 (C), 150.1 (C), 149.7 (2×CH), 140.6 (C), 120.6 (2×CH), 98.9 (-C≡C-),
3
C
9
7.4 (-C≡C-), 96.0 (C3), 61.6 (C6), 43.0 (C5), 38.5 (C4), 28.1 (C5a,b), 0.0 (TMS). FTIR
(
neat): 3043, 3031, 2962, 2934, 2910, 2877, 2848, 2153, 1597, 1535, 1487, 1465, 1450,
+
1
432, 1418, 1370, 1316, 1273, 1247, 1216, 1177, 1066, 988. HRMS (ESI) m/z: [M + H]
Calcd. for C H N Si: 310.1734. Found: 310.1729.
18 23
3
3
-Ethynyl-5,5-dimethyl-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (5h). 5g
(500 mg, 1.62 mmol) was dissolved in anhydrous MeOH (10 mL). K CO (223 mg, 1.62
2
3
mmol) was added and the solution was stirred for 0.5 h at rt under an argon
atmosphere. The solid residue was filtered and washed with MeOH (3×5 mL). The
solvent was evaporated and the crude product was purified by column chromatography
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(
EtOAc) affording 383 mg, 97% of a colorless solid; mp 140.6–141.0 °C. H NMR (CDCl ):
3
3
3
δ 8.54 (d, J = 4.6, 2H, 2×CH), 7.93 (d, J = 4.6, 2H, 2×CH), 7.26 (s, 1H, ≡CH), 3.84 (s, 2H,
H
13
1
H6), 2.72 (s, 2H, H4), 1.23 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 152.5 (C), 150.8 (C),
3
C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
4
1
49.8 (2×CH), 140.7 (C), 120.4 (2×CH), 94.8 (-C≡CH), 81.8 (C3), 77.4 (-C≡CH), 61.6 (C6),
3.0 (C5), 38.4 (C4), 28.1 (C5a,b). FTIR (neat): 3095, 2957, 2936, 2911, 2872, 1602, 1533,
485, 1466, 1445, 1431, 1421, 1401, 1370, 1322, 1266, 1236, 1216, 1178, 1066, 996.
+
HRMS (ESI) m/z: [M + H] Calcd. for C H N : 238.1339. Found: 238.1333.
1
5 15 3
Preparation of 5i and 5j. 5h (100 mg, 0.421 mmol), aryl iodide (1.2 equiv.), CuI (10
mol%), Pd(PPh ) Cl (5 mol%) and Et N (3 equiv.) were dissolved in anhydrous MeCN
3
2
2
3
(2.5 mL). The mixture was stirred at 70 °C under an argon atmosphere for 1 h. MeCN
was evaporated and the crude products were purified and finally crystallized from
MeCN.
5
,5-Dimethyl-3-(pyridin-2-ylethynyl)-2-(pyridin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazole (5i). Column chromatography (MeOH/DCM 1:15) afforded 110 mg, 83% of
1
light yellow solid; mp 105.5–106.2 °C. H NMR (CDCl ): δ 8.59–8.63 (m, 1H, CH), 8.11
3
H
(bs, 4H, 4×CH), 7.62–7.70 (m, 1H, CH), 7.42–7.48 (m, 1H, CH), 7.18–7.24 (m, 1H, CH),
1
3
1
3
1
.94 (s, 2H, H6), 2.87 (s, 2H, H4), 1.32 (s, 6H, H5a,b). C { H} NMR (CDCl ): δ 153.0 (C),
3 C
50.8 (C), 150.2 (CH), 150.0 (2×CH), 143.7 (C), 140.5 (C), 136.3 (CH), 127.0 (CH), 122.8
(CH), 120.8 (2×CH), 95.2 (-C≡C-), 93.0 (-C≡C-), 81.8 (C3), 61.9 (C6), 43.3 (C5), 38.9 (C4),
2
8.3 (C5a,b). FTIR (neat): 3069, 3035, 2993, 2955, 2929, 2878, 2852, 2222, 1598, 1580,
1559, 1541, 1491, 1462, 1439, 1420, 1389, 1371, 1333, 1303, 1280, 1265, 1217, 1175,
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