5-Carboxymethyl-2-(4-methylthiophenyl)-1,3,2-dioxaborolan-4-one: Synthesis, characterization and application in enantioselective reduction of ketones

Article abstract of DOI:10.1002/aoc.1757

The reaction of arylboronic acids with L-O-benzoyl-tartaric acid and D,L-malic acid has been studied. The obtained (acyloxy)boranes are moderately stable in solution and decompose to give boroxines. 5-Carboxymethyl-2-(4- methylthiophenyl)-1,3,2-dioxaborolan-4-one was obtained in the reaction of 4-methylthiophenylboronic acid with D,L-malic acid and characterized by X-ray structural analysis. The use of L-(-)-malic acid afforded the optically pure product which can be used as the powerful chiral reagent in the enantioselective reduction of ketones.

Full text of DOI:10.1002/aoc.1757

Full Paper
Received: 19 August 2010
Revised: 19 October 2010
Accepted: 19 October 2010
Published online in Wiley Online Library: 14 January 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1757
5-Carboxymethyl-2-(4-methylthiophenyl)-
1,3,2-dioxaborolan-4-one: synthesis,
characterization and application in
enantioselective reduction of ketones
a
b
a∗
a
´
´
Agnieszka Gorska , Halina Hajmowicz , Tomasz Klis , Janusz Serwatowski
and Ludwik Synoradzkib
The reaction of arylboronic acids with L-O-benzoyl-tartaric acid and D,L-malic acid has been studied. The obtained
(acyloxy)boranesaremoderatelystableinsolutionanddecomposetogiveboroxines.5-Carboxymethyl-2-(4-methylthiophenyl)-
1,3,2-dioxaborolan-4-one was obtained in the reaction of 4-methylthiophenylboronic acid with D,L-malic acid and characterized
by X-ray structural analysis. The use of L-(−)-malic acid afforded the optically pure product which can be used as the powerful
c
chiral reagent in the enantioselective reduction of ketones. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: (acyloxy)boranes; boronic acids; tartaric acid; malic acid
1
1
Introduction
with the H-NMR spectrum of 1: H-NMR (dmso-d6, 400 MHz) δ
13.23 (s, 2H), 8.04 (d, 2H), 7.68 (t, 1H, J = 6.8 Hz), 7.54 (d, 2H),
6.00 (s, OH), 5.48 (d, C–H, J = 2.4 Hz), 4.68 (d, C–H) revealed
the presence of the unreacted starting material. Integration of
the C–H signals revealed that the reaction yield varies in the
range 40–60% depending on boronic acid used. These results
were supported by the 11B and 19F-NMR resonances. The 11B-
NMR spectra in dmso-d6 revealed the presence of two broad
signals at 30 and 11 ppm respectively. The signal at 11 ppm
resulted from the presence of tetravalent boron atom in the
CAB*DMSOadduct.The19F-NMRspectrumof3bshowed2singlets
at −60.80 and −61.31 ppm. The formation of the mixture caused
problems in isolation and purification of products. However, the
formation of 3a–d was confirmed by MS spectra. Concentration
of the reaction mixture containing 3d followed by cooling to
−15 ◦C afforded colorless crystals after 2 weeks. Unexpectedly,
the analysis revealed the presence of the boroxine (2-F-C6H4BO)3,
4d. According to our hypothesis the formation of 4d can be
initiated by the intramolecular protonation of the oxygen atom
and the subsequent substitution on the carbonyl carbon atom
(Scheme 2).
Reaction of arylboronic acids with tartaric acid derivatives oc-
curs with formation of chiral (acyloxy)boranes (CAB), which have
attracted great attention for their catalytic formation ability of
complex carbocyclic frameworks in an enantiomerically enriched
form.[1] The application of CAB involves the formation of di-
hydropyrone derivatives,[2] 3-cyclohexene-1-carboxaldehydes[3,4]
and 1,4-bicyclo-2,5-diene-carboxaldehydes[5] via Diels–Alder re-
actions, Sakurai–Hosomi reaction,[6] synthesis of homoallylic
alcohols[7] and β-hydroxyesters[8] in Aldol-type reactions,[9]
polyaddition of bis(allyl)silanes and dialdehydes.[10] These reac-
tions proceed smoothly and require usually 10–20 mol% of the
CAB complex. The enantiomeric excess is strongly dependent on
the substituent at the phenyl ring bonded to the boron atom.
Despite some work on the mechanism of catalysis,[11,12] there
is a lack of study on the formation and structure of the cat-
alyst. The CABs have been synthesized without isolation and
used immediately in the reactions. The proposed structure is
based on the molecular weight, found cryoscopically in ben-
zene, and the carbonyl absorption at 1821 cm−1 characteristic
of the five-membered ring carbonyl compound.[1] In this work
we present our results on the reaction of arylboronic acids
with L-O-benzoyl-tartaric acid and D,L-malic acid. We obtained
and fully characterized 5-carboxymethyl-2-(4-methylthiophenyl)-
1,3,2-dioxaborolan-4-one, the first crystalline CAB.
The difficulties in the synthesis of CAB using 1 prompted us to
look for a simpler hydroxy-carboxylic acid and we decided to use
D,L-malic acid. The reactions of 1a with arylboronic acids 2a and
2b were carried out in THF solution using CaH2 to remove water
We were interested in the preparation of the CAB catalysts 3a–d
derived from the L-O-benzoyl-tartaric acid 1 and arylboronic acids
2a–d (Scheme 1). Thus, the equimolar amounts of the reagents
were dissolved in THF at room temperature to form the clear
solutions. After 24 h the samples of the reaction mixtures were
collected and evaporated. The remaining solids were dissolved in
dmso-d6. The 1H-NMR showed the presence of four signals in the
range of 4.6–5.6 ppm. The comparison of the obtained spectra
∗
´
Correspondence to: Tomasz Klis, Physical Chemistry Department, Faculty of
Chemistry,WarsawUniversityofTechnology,Noakowskiego3,00-664Warsaw,
Poland. E-mail: ktom@ch.pw.edu.pl
a
Physical Chemistry Department, Faculty of Chemistry, Warsaw University of
Technology, Noakowskiego 3, 00-664 Warsaw, Poland
b
LaboratoryofTechnologicalProcesses,FacultyofChemistry,WarsawUniversity
of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
c
Appl. Organometal. Chem. 2011, 25, 294–297
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

5-Carboxymethyl-2-(4-methylthiophenyl)-1,3,2-dioxaborolan-4-one
Scheme 1. General reaction scheme for the reaction of arylboronic acids with L-O-benzoyl-tartaric acid and malic acid.
Scheme 2. The mechanism of the formation of boroxines.
Scheme 3. The influence of the ring strain on the reaction rate.
from the reaction system. The reaction progress was controlled
by measurement of the amount of the hydrogen evolved. After
the reaction was completed, the reaction mixture was decanted
from CaH2 and concentrated. For the reaction of 1a with 2b, the
concentration gave the thick oil which solidified after 1 h under
vacuum, whereas for the reaction of 1a with 2a, the crystalline
solid was obtained after removal of ca 25% of the solvent. The
1H-NMR spectra revealed that 3e and 3f were formed selectively.
Single crystals of 3e were obtained by slow concentration of the
reaction mixture.
The X-ray structure determination of 3e revealed that the
boron atom is involved in a five-membered ring which is essen-
tially flat and coplanar with the benzene ring and thiomethyl
group (Fig. 1). The carboxylic group is endo-oriented to the
five-membered ring with the carbonyl oxygen atom positioned
towards the ring center. The angle O5–C4–C3 is significantly
declined from the value 120◦ characteristic for sp2 hybridized
carbon atom, which results in the ring tension. This fact in-
fluences strongly the kinetics of the formation of 3e. In two
independent experiments 2a was reacted with 1a or with tar-
taric acid[13,14] and the rate of the hydrogen evolution was
controlled. The experiments revealed that reaction with 1a is
much slower than the reaction with tartaric acid (Scheme 3).
The explanation lies in the rising of the ꢀG‡ in the forma-
tion of 3e because of the introduction of the ring strain. The
five-membered ring in 5 is not strained because of the pres-
ence of two sp3 hybrydized carbon atoms. Although the crystal
structure of many boronic acids like 4-tolylboronic acid or its
catechol ester have been already published,[15–17] the number
of crystal structures of aromatic organo-oxyboranes containing
sulfur atoms is limited to 2-benzylthiophenylboronic acid which
forms characteristic dimers through hydrogen bonds.[18] How-
ever, the structures of 4-methylthiophenyl-bis-mesitylborane[19]
and related sulfur-containing triarylboranes were also recently
published.[20,21]
The new (acyloxy)borane 3e is moderately stable in air. It
forms a strong adduct with DMSO which results in significant
changes in the NMR spectra. In the IR spectrum of 3e we found
the absorption peak at 1800 cm−1. This value differs from the
1821 cm−1 frequency reported for the other CABs. The reactivity
of the optically active 3e obtained from L-(−)-malic acid was
tested in the reduction of ketones in the presence of NaBH4.[14]
c
Appl. Organometal. Chem. 2011, 25, 294–297
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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A. Go´rska et al.
Table 1. Reduction of acetophenones using 3e–NaBH4 system
Ketone
Product
Yield, e.e. (configuration)
96%; 99.5% (R)
94%; 99.2% (R)
84%; 95.6% (R)
81%, 87.1% (R)
The reduction of selected acetophenones yielded the respective
secondary alcohols with high enantioselectivity (Table 1).
Inconclusion,thereactionofarylboronicacidswithL-O-benzoyl-
tartaric acid afforded the respective CAB in moderate yields. The
reaction of 4-methyltiophenylboronic acid with D,L-malic acid oc-
curs selectively in the THF–CaH2 system to give 5-carboxymethyl-
2-(4-methylthiophenyl)-1,3,2-dioxaborolan-4-one. The presented
procedure can be the general way to synthesize (acyloxy)boranes
from malic acid. The use of L-(−)-malic enables the synthesis of
the optically active 3e, which shows remarkable reactivity in the
enantioselective reduction of acetophenones.
Figure 1. Structure of 3e with thermal ellipsoids at the 50% prob-
ability level. Selected bond lengths (Å) and angles (deg): B1–C5
1.539(3), B1–O51.406(3), C4–O4 1.983(2), C4–C31.519(3), C4–O5 1.366(2),
C3–O31.441(2), O5–C4–O4 123.01(2), O5–C4–C3 107.90(2), C4–C3–O3
104.31(2), O2–C1–O1 124.18(2), O4–C4–C3 129.02(2), C3–C2–C1–O2
37.33(3). Crystallographic data for this structure have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 781172.
Experimental Section
1H-, 13C-, 19F- and 11B-NMR as well as IR spectra were recorded
at room temperature. Chemical shifts are given in ppm relative
1
to TMS in H- and 13C-NMR spectra, relative to C6F6 in 19F-NMR
spectra and relative to Et2O*BF3 in 11B-NMR spectra. All chemicals
were received from Aldrich. THF was stored over sodium and
DMSO-d6 was distilled over CaH2 prior to use. All reactions were
carried out under dry argon using standard Schlenk techniques.
The enantiomeric excess was measured using S(+)-α-methoxy-α-
trifluoromethyl-phenylacetic acid chloride as the chiral selector.
The absolute configurations were obtained by comparison of
opticalrotationwithvaluesmeasuredforenantiopurecompounds
obtained from Aldrich.
the vigorous stirring. The reaction flask was tightly closed and only
the connection to the gas evolution measurement apparatus was
left open. The reaction started immediately, which was indicated
as the rapid gas evolution. The reaction mixture was left on stirring
until the stoichiometrical amount of hydrogen evolved (ca 24 h).
After this time the stirrer was turned off and the reaction mixture
was left to clarify (ca 48 h). A clear solution over precipitate was
obtained. This solution was transferred to another reaction flask
via cannula. Concentration of this solution by 25% under vacuum
at room temperature afforded colorless crystals. The crystals were
separated and the remaining solution was placed to the freezer
(−15 ◦C). After 2 days the new portion of crystals was obtained.
Both of the fractions were combined and dried under vacuum
Synthesis of 3e†
4-Methylthiophenylboronic acid (1.68 g, 0.01 mol), D,L-malic acid
(1.34 g, 0.01 mol) and CaH2 (1.68 g, 0.04 mol) were placed in the
reaction flask and THF (40 ml) was added via a syringe maintaining
† PL patent applied for
c
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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Appl. Organometal. Chem. 2011, 25, 294–297

5-Carboxymethyl-2-(4-methylthiophenyl)-1,3,2-dioxaborolan-4-one
to obtain 3e. Yield: 2.7 g (92%). 1H-NMR (THF-d8, 400 MHz) δ
7.66 (d, 2H, J = 4.4 Hz), 7.20 (d, 2H), 4.82 (dd, 1HX, J = 4.4 Hz,
J = 4.8 Hz), 2.90 (dd, 1HA, J2 = 11.2 Hz, J3 = 4.4 Hz), 2.83 (dd,
1HB, J2 = 11.2 Hz, J3 = 4.8 Hz), 2.41 (s, 3H). 13C-NMR (THF-d8,
100 MHz) δ 176.30 (COOH), 171.29 (C O), 146.57 (CAr –S), 136.25
(CAr), 125.91 (CAr), 74.12 (C–H), 36.64 (CH2), 14.81 (CH3). 11B-NMR
(THF-d8, 64 MHz) δ 32. MS, EI–HR: calcd for C11H11O5BS 266.04203.
Found: 266.04311. Elemental analysis: calcd for C11H11O5BS: C,
49.65; H,4.17. Found: C, 49.96; H,4.21.
solved using direct methods, and refined with the full-matrix least-
squares technique using the SHELXS97 and SHELXL97 programs,
respectively. C11H11O5BS*C4H8O, FW = 338.17, monoclinic, space
group P21/c, Dcalcd = 1.399 g cm−3, Z = 4, a = 12.6498(3) Å,
b = 5.43210(13) Å, c = 23.5827(5) Å, α = 90.00◦, β = 97.667(2)◦,
γ = 90.00◦, V = 1606.00(7) Å3, T = 100(2) K, Gemini A Ultra
Diffractometer, λ (Cu/Kα) = 1.5418 Å, µ = 2.041 mm−1. Of 10 319
reflectionsmeasured,1993wereunique(Rint = 0.045).Refinement
on F2 concluded with the values R1 = 0.0490 and wR2 = 0.0892
for 226 parameters and 2502 data with I > 2δI.
Synthesis of 3e*DMSO-d6
Acknowledgments
3e (0.021 g) was dissolved in DMSO-d6 (0.6 ml) to form the clear
solution. 1H-NMR (DMSO-d6, 400 MHz) δ 7.31 (d, 2H, J = 6.4 Hz),
7.11 (d, 2H), 4.50 (dd, 1HX, J3 = 4.0 Hz, J3 = 4.4 Hz), 2.67 (dd,
1HA, J2 = 15.2 Hz, J3 = 4.0 Hz), 2.45 (dd, 1HB, J2 = 15.2 Hz,
J3 = 4.4 Hz), 2.41 (s, 3H). 13C-NMR (DMSO-d6, 100 MHz) δ 177.68
(COOH), 171.90 (C O), 140 (C–B, br), 136.36 (CAr –S), 132.27 (CAr),
125.17 (CAr), 71.87 (CH), 39.01 (CH2), 15.01 (CH3). 11B-NMR (DMSO-
d6, 64 MHz) δ 11. Elemental analysis: calcd for C13H11D6O6BS2: C,
44.58; H,6.62. Found: C, 44.76; H,6.69.
This work was supported by the Warsaw University of Technol-
ogy. The X-ray measurements were undertaken in the Inorganic
Chemistry Laboratory, Chemistry Department, Warsaw University
of Technology. Support from Aldrich Chemical Company, Milwau-
kee, WI, USA, through the donation of chemicals and equipment
is gratefully acknowledged.
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3e obtained from L-(−)-malic acid (1.01 g, 0.003 mol) and
4-fluoroacetophenone (0.41 g, 0.003 mol) was placed in the
Schlenk flask and THF (30 ml) was added maintaining the stirring.
NaBH4 (0.11 g, 0.003 mol) was added to the obtained solution
causing the rapid gas evolution. After 1 h the reaction mixture
was poured onto water (50 ml) and extracted with hexane (30 ml).
The organic phase was dried with MgSO4 and evaporated to give
4-fluoro-α-methylbenzyl alcohol. 1H-NMR (CDCl3, 400 MHz) δ 7.23
(m, 2H), 6.93 (m, 2H), 4.77 (q, 1H), 2.06 (br, 1H), 1.36 (d, 3H). 13C-NMR
(CDCl3, 100 MHz) δ 161.3 (d, JC1 –F = 253 Hz), 136.5, 128.1, 115.7,
75.7, 22.6. Elemental analysis: calcd for C8H9OF: C, 68.56; H,6.47.
Found: C, 69.01; H,6.56.
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and S(+)-α-methoxy-α-trifluoromethyl-phenylacetic acid chloride
were placed into vial and dissolved in 0.2 ml of hexane. The excess
of K2CO3 was added and the obtained mixture was kept at 50 ◦C
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Single crystal data were collected on a Gemini A Ultra Diffrac-
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empirical absorption corrections using spherical harmonics, im-
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c
Appl. Organometal. Chem. 2011, 25, 294–297
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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