Development of an efficient process for 3,6-dihydro-2h-pyran-4-boronic acid pinacol ester

Article abstract of DOI:10.3987/COM-15-13255

An efficient process for the synthesis of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester has been developed in one-pot manner. Starting from the condensation of 4-tetrahydropyranone with hydrazine hydrate, the subsequent treatment of hydrazone with copper(II) bromide-triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) conveniently gave 4-bromo-3,6-dihydro-2H-pyran, which was then conducted through palladium-catalyzed borylation to afford the desired product using a low loading of a Pd catalyst.

Full text of DOI:10.3987/COM-15-13255

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HETEROCYCLES, Vol. 91, No. 8, 2015
HETEROCYCLES, Vol. 91, No. 8, 2015, pp. 1654 - 1659. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 25th May, 2015, Accepted, 29th June, 2015, Published online, 10th July, 2015
DOI: 10.3987/COM-15-13255
DEVELOPMENT
OF
AN
EFFICIENT
PROCESS
FOR
3,6-DIHYDRO-2H-PYRAN-4-BORONIC ACID PINACOL ESTER
Feng Xue,* Yong Zhu, and Chang-Gong Li
Key Laboratory of Functional Organic Molecules of Xinxiang City Henan
Province, College of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang Henan, 453002, P. R. China. E-mail:
fxuehist@sina.com
Abstract
–
An
efficient
process
for
the
synthesis
of
3,6-dihydro-2H-pyran-4-boronic acid pinacol ester has been developed in one-pot
manner. Starting from the condensation of 4-tetrahydropyranone with hydrazine
hydrate, the subsequent treatment of hydrazone with copper(II)
bromide-triethylamine
and
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)
conveniently gave 4-bromo-3,6-dihydro-2H-pyran, which was then conducted
through palladium-catalyzed borylation to afford the desired product using a low
loading of a Pd catalyst.
In the search for biologically active compounds as potential drug candidates, the efficient synthesis of
both libraries and individual heterocyclic small molecules is of major importance to the pharmaceutical
industry. 1-Alkenylboron derivatives are an important class of compounds in synthetic organic
chemistry,1 the utility of which has been amply demonstrated in the synthesis of natural products,
biologically active compounds, and functional organic materials by application of numerous
carbon-carbon bond forming reactions, such as Pd-catalyzed cross-coupling with organic electrophiles,2
Rh-catalyzed addition to carbonyl substrates,3 Matteson homologation,4 and Petasis reaction with amine
and carbonyl compounds.5 Of a variety of such compounds, 3,6-dihydro-2H-pyran-4-boronic acid pinacol
ester is a versatile synthetic intermediate used in palladium-catalyzed Suzuki-Miyaura cross-coupling
reaction for the preparation of a wide variety of natural products and biologically active compounds, such
as pyridine-2-amide6 and polycyclic indazole derivatives7 (Scheme 1). These compounds exhibit various
types of significant biological properties, such as anti-HIV, antituberculosis, anticancer,
antimycobacterial.

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For example, the pyridine-2-amide compounds are preferential agonists of the Cannabinoid Receptor 2
which are particularly useful in the treatment or prophylaxis of pain.
Scheme 1. Representative compounds based on 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 1
Up to now, some successes have been made in the preparation of 3,6-dihydro-2H-pyran-4-boronic acid
pinacol ester, typical examples included Masuda’s palladium-catalyzed borylation of alkenyl triflates (or
iodides) with pinacolborane,8 Scott’s ruthenium-catalyzed olefin metathesis with the 2nd generation
Grubbs’ catalyst.9 Although these procedures have shown some practical applications in synthesis, their
application has still been limited and deficient in view of laborious synthetic process, harsh reaction
conditions and relatively expensive reagents. Considering that the great importance of
3,6-dihydro-2H-pyran-4-boronic acid pinacol ester in synthesis, it is desired to find another efficient
process to satisfy both laboratory and industrial operations. As an extension of our program dealing with
the preparation of boric acid esters of biological interest,10 we herein described an efficient process for the
preparation of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester. With smooth and simple reaction
procedures from 4-tetrahydropyranone, this method of synthesis provided easy access to the target
compound.
During the investigation of palladium-catalyzed borylation of alkenyl triflate (or iodides) with
pinacolborane by Masuda and co-workers,8,11 instead of a small amount of the expected
pyranalkenylboronate 1, the authors observed its isomeric allylic boronate as the major product. Another

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HETEROCYCLES, Vol. 91, No. 8, 2015
method by Scott and co-workers,9 was, however, still problematic because it involved a multistep reaction
route and hence the yield of terminal product was unsatisfactory. To develop more efficient method for
the preparation of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 1 with advantage of simplicity,
safety, and inexpensiveness, our attention was attracted to a report by Takeda and co-workers12 on the
transformation of ketones to gem-dihalides via hydrazones using copper(II) halides, the authors pointed
out that the preparation of hydrazones by the treatment of carbonyl compounds with hydrazine hydrate
using molecular sieves as a dehydrating agent was conducive to avoid the formation of the corresponding
azines. But in the course of our study on the preparation of hydrazones, we found that almost quantitative
relatively pure (dihydro-2H-pyran-4(3H)-ylidene)hydrazine 9 was easily achieved by the treatment of
4-tetrahydropyranone 8 with hydrazine hydrate without adding molecular sieves, thus bypassing the use
of molecular sieves, which simplified the procedure without a decrease of the yield. On the other hand,
when the oxidation of hydrazone 9 using copper(II) bromide-triethylamine in methanol to give
gem-dibromide was completed, the subsequent intramolecular elimination reaction of gem-dibromide
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene could conveniently afford relatively pure
4-bromo-3,6-dihydro-2H-pyran 10 after simple aqueous work-up, which were removed of volatile
materials and employed for the further cross-coupling reaction without any purification. It was reasonable
to assume that the improved preparation of 10 from 8 without a relatively harsh process was more safe
and efficient as compared with the previously reported procedure,13 thus making the reaction facile and
easy to scale-up. In the final palladium-catalyzed borylation reaction of bis(pinacolato)diboron and 10,
Miyaura et al. mentioned that stronger base such as PhOK instead of KOAc, K2CO3 was beneficial to
eliminate Heck product and the dimer product with tolune as solvent.14 Through exploration of reaction
conditions, we found that a low loading of 1% mmol Pd catalyst was economical and satisfactory with
KOAc as base additive in dioxane, and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 1 was
smoothly obtained in 66% yield at 80 °C for 3 h.
Scheme 2. Synthesis of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 1
DBU
=
1,8-diazabicyclo[5.4.0]undec-7-ene, B2pin2
=
bis(pinacolato)diboron, PdCl2dppf
=
1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloride methylene chloride complex.

HETEROCYCLES, Vol. 91, No. 8, 2015
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In conclusion, we report an improved and efficient process for the preparation of
3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with smooth and simplified reaction procedures.
Preparation of 4-bromo-3,6-dihydro-2H-pyran through oxidation and subsequent elimination of
(dihydro-2H-pyran-4(3H)-ylidene)hydrazine, which was easily prepared by the treatment of
4-tetrahydropyranone with hydrazine hydrate without molecular sieves 4Å, with copper(II)
bromide-triethylamine and DBU was developed, and the next borylation by 1% mol Pd catalyst produced
the target product in 66% yield. The advantages of this improved method are its preparative ease and its
efficiency without laborious procedures. Compared with the reported procedures, the overall process is
more economical as well as effective, which will satisfy both laboratory and industrial operations.
EXPERIMENTAL
Solvents and reagents were purchased and used without further purification. Melting points were
determined on a Mettler FP5 melting point apparatus and are uncorrected. NMR spectra were recorded on
Bruker DRX 400 MHz spectrometer using CDCl3 as solvent, and tetramethylsilane (TMS) as internal
standard. High resolution mass spectra were recorded on Applied Biosystems Mariner System 5303.
(Dihydro-2H-pyran-4(3H)-ylidene)hydrazine (9). 50 g of hydrazine hydrate, and 80 mL of anhydrous
EtOH were added successively with stirring in a flask, After 10 min, EtOH (50 mL) solution of
4-tetrahydropyranone 8 (20 g, 0.2 mol) was added dropwise to the reaction mixture at rt and the mixture
was stirred for additional 30 min. When the reaction was completed, the mixture was diluted with CH2Cl2
(150 mL), and transferred into a 500-mL separatory funnel, then rinsed with CH2Cl2 (3 × 50 mL). The
combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to
give the corresponding crude hydrazone 9 as colorless liquid (22.1 g, 96% yield), which was suitable for
use in the next step without further purification.
4-Bromo-3,6-dihydro-2H-pyran (10). Under an atmosphere of nitrogen, to MeOH (400 mL) solution of
copper(II) bromide (134 mg, 0.6 mol) was added triethylamine (42 mL, 0.3 mol) at 20 oC and the reaction
mixture was stirred for 10 min at the same temperature. The mixture was cooled to 0 oC, and MeOH (150
mL) solution of hydrazone 9 (11.4 g, 0.1 mol) was added dropwise over 10 min, and then stirring was
continued for 1 h. The reaction was quenched by addition of 10% aqueous NH3 solution, filtered over
Celite, and organic materials were extracted with CH2Cl2, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give a pale yellow oily residue (24.0 g) which was dissolved in
toluene (300 mL), and DBU (22.8 g, 0.15 mol) was added. Then the reaction mixture was stirred for
further 1 h, and treated with 5% HCl until pH = 2 was reached, the resulted mixture was stirred for
another 0.5 h, and the aqueous layer was separated and then extracted with CH2Cl2. The organics were
combined, washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give

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crude 4-bromo-3,6-dihydro-2H-pyran 10 as colourless oil (15.1 g, 93% yield), which was relatively pure
1
enough to employ for the further reaction without any purification. H NMR (400 MHz, CDCl3): δ 6.07
(m, 1H), 4.20–4.13 (m, 2H), 3.86–3.82 (m, 2H), 2.56–2.49 (m, 2H).
3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (1). Under an atmosphere of nitrogen, a solution of
4-bromo-3,6-dihydro-2H-pyran 10 (24.5 g, 0.15 mol), bis(pinacolato)diboron (42.0 g, 0.15 mol),
1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloride methylene chloride complex (1.25 g, 1.5
mmol) and potassium acetate (44.5 g, 0.45 mol) in dioxane (350 mL) was heated to 80 oC for 3 h. Water
(50 mL) was added to the reaction mixture which then was extracted with CH2Cl2 (3 x 30 mL). The
combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The residue was recrystallized in cold hexane to yield the title compound 1 (20.6
1
g, 0.098 mol, 66% yield) as white solid. mp 61–62 °C (lit.11 60–61 °C); H NMR (400 MHz, CDCl3): δ
6.53 (s, 1H), 4.20–4.18 (m, 2H), 3.77–3.74 (t, J = 6 Hz, 2H), 2.25–2.23 (m, 2H), 1.27 (s, 12H); HRMS
calcd for C11H19BO3 [M]+ 210.1427; found: 210.1429.
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (21371148).
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