The preparation of optically active boronic ester substituted Δ2-isoxazolines

Article abstract of DOI:10.1016/S0022-328X(99)00055-8

In this paper we report our recent results in the area of nitrile oxide cycloaddition to optically active vinylboronic esters to afford optically active boronic ester substituted Δ²-isoxazolines. In these studies, a number of optically active d

Full text of DOI:10.1016/S0022-328X(99)00055-8

Journal of Organometallic Chemistry 581 (1999) 87–91
The preparation of optically active boronic ester substituted
D2-isoxazolines
Richard H. Wallace a,b,*, K.K. Zong b
a Department of Chemistry and Physics, Armstrong Atlantic State Uni6ersity, Sa6annah, GA 31419, USA
b Department of Chemistry, Uni6ersity of Alabama, Tuscaloosa, AL 35487, USA
Received 30 June 1998; received in revised form 14 December 1998
Abstract
In this paper we report our recent results in the area of nitrile oxide cycloaddition to optically active vinylboronic esters to
afford optically active boronic ester substituted D2-isoxazolines. In these studies, a number of optically active diols were
investigated and TADDOLs have been found to afford the best diastereoselectivity. The mixture of diastereomers obtained in
these reactions can be readily purified by formation of the diethanolamine–boron complexes and recrystallized to afford the pure
enantiomers. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Asymmetric synthesis; Boronic esters; Cycloadditions; Isoxazolines; Nitrile oxides
1. Introduction
that of the boronic ester, by carrying out nitrile oxide
cycloadditions with optically active vinylboronic esters
to afford optically active boronic ester substituted D2-
isoxazolines [4].
The D2-isoxazolines produced by the 1,3-dipolar cy-
cloaddition of a nitrile oxide to an alkene have proven
to be extremely useful compounds in organic chemistry
[1a,b,c,d]. Among the various classes of compounds
which have been prepared from these cycloadducts are
enones [1a], 1,3 amino-alcohols [1e], and i-hydroxy
ketones [1a]. The boronic ester functionality has also
enjoyed considerable use in organic synthesis [2a,b].
Procedures exist for the direct conversion of boronic
esters into alcohols [2b], aldehydes [2b,c], carboxylic
acids [2b,c], and amines [2b,c]. It has also been shown
that it is possible to homologate boronic esters by
inserting a methylene into the carbon–boron bond
[3a,b,c]. The ability to carry out the homologation of a
boronic ester coupled with the large number of func-
tional groups which it represents has resulted in the
boronic ester becoming an extremely versatile func-
tional group. We report in this paper our recent results
which combine the usefulness of the D2-isoxazoline with
We have shown previously that vinylboronic esters
are very reactive dipolarophiles in nitrile oxide cycload-
ditions [5a,b] and the resulting boronic ester containing
D2-isoxazolines can be transformed into a variety of
useful products [6]. Our goal in this project was to
extend this methodology to allow for the preparation of
optically active boronic ester containing D2-isoxazoli-
nes. There are several methods by which this could, be
undertaken. One approach involves the use of an opti-
cally active diol as a chiral auxiliary on the boronic
ester functional group. Nitrile oxide cycloaddition to
the vinylboronic ester would afford the D2-isoxazoline
as a mixture of diastereomers (Eq. (1)). Another option
would be to place the chiral auxiliary elsewhere in the
vinylboronic ester. We recently reported the use of a
camphorsultam substituted vinylboronic ester in this
approach [7a,b].
* Corresponding author. Tel:. +1-912-921-5655; fax: +1-912-961-
3226.
E-mail address: richard wallace@marlgate.armstrong.edu (R.H.
Wallace)
–
(1)
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00055-8

88
R.H. Wallace, K.K. Zong / Journal of Organometallic Chemistry 581 (1999) 87–91
The route depicted in Eq. (1) seems particularly attrac-
tive in light of the elegant work of Matteson and
coworkers employing chiral diols as ligands on boronic
esters [2a] and because of the large number of optically
active diols available. Our initial efforts in this project
were directed at exploring optically active 1,2-diols as
chiral auxiliaries in this reaction. Some of the optically
active 1,2-diols explored in this reaction include pinane-
diol (1) [2a], di-isopropyl tartrate (2), dihydrobenzoin
(3) and a diol prepared in our laboratories [8] for use as
a ligand for titanium catalysts (4).
THF afforded the binaphthol substituted optically ac-
tive vinylboronic ester (8) (Eq. (4)). Nitrile oxide cy-
cloaddition of benzonitrile oxide (6) with (8) afforded
the D2-isoxazoline as a 2:1 mixture of diastereomers.
Reactions employing vinylboronic ester (8) proved
difficult to carry out due to the inherent instability of
this compound towards hydrolysis of the binaphthol
unit. It also proved difficult to determine the
diastereoselectivity of this reaction from the crude reac-
tion mixture due to the tendency of the binaphthol
ligand to undergo hydrolysis during the work-up proce-
dure. In an effort to develop a reliable method for the
determination of the diastereoselectivity in this reaction
the exchange of binaphthol with pinanediol (1) was
explored. This exchange reaction proved to be ex-
tremely rapid and complete replacement of the binaph-
thol with pinanediol was readily accomplished. The
ratio of diastereomers could be easily determined by
1
examination of the H-NMR spectra of the pinanediol
containing boronic ester substituted D2-isoxazolines.
This exchange afforded a quick, easy, and reliable
method for the determination of the diastereoselectivity
in these cycloadditions. Although binaphthol proved to
be a more efficient chiral auxiliary than the 1,2-diols
studied, the moisture sensitivity of 7 and 8 along with
the difficulty associated with their preparation made the
exploration of other chiral auxiliaries attractive.
Preparation of the optically active vinylboronic esters
was readily accomplished by treatment of the 1,2-diol
with dibutyl vinylboronate [9] in an ether/pentane mix-
ture at room temperature. An example of this transes-
terification employing pinanediol (1) is shown in Eq.
(2).
(2)
Nitrile oxide cycloaddition of benzonitrile oxide (6)
with (5) afforded the D2-isoxazoline in 94% yield as a
1:1 mixture of diastereomers (Eq. (3)). All other opti-
cally active 1,2-diols explored in this reaction also
afforded the cycloadduct in high yield but gave very
low levels of diastereoselectivity. Based on the low
levels of diastereoselectivity obtained with 1,2-diols we
decided to explore the use of 1,4-diols as chiral auxil-
iaries in this reaction.
(4)
TADDOLs have been shown to be very effective
chiral auxiliaries in a wide variety of organic reactions
[11a,b]. The preparation of the TADDOL substituted
vinylboronic ester (9) was easily accomplished by reac-
tion of the TADDOL with vinylboronic anhydride–
pyridine complex [12] in toluene at reflux (Eq. (5)).
(5)
(3)
Nitrile oxide cycloaddition of benzonitrile oxide (6)
with (9) proceeded smoothly to afford the cycloadduct
as a 2:1 mixture of diastereomers. It again proved
difficult to accurately determine the diastereoselectivity
on the crude reaction mixture owing to the tendency of
the TADDOL to undergo hydrolysis during work-up.
Treatment of the crude cycloaddition mixture with
pinanediol afforded the pinanediol containing boronic
ester substituted D2-isoxazoline. The determination of
Binaphthol [10] and TADDOLs [11a,b] have been
shown to be very effective chiral auxiliaries in a variety
of reactions. Attempts to prepare the binaphthol substi-
tuted vinylboronic ester by reaction of binaphthol with
dibutyl vinylboronate [9] or vinylboronic anhydride–
pyridine complex [12] proved to be troublesome and an
alternative method was explored. Reaction of bis-
(dimethylamino)vinyl borane (7) and binaphthol in

R.H. Wallace, K.K. Zong / Journal of Organometallic Chemistry 581 (1999) 87–91
89
crystallizing the diethanolamine–boron complexes as a
means of separating the isomers obtained in the reac-
tion [2b]. This allowed purification of the mixture of
isomers obtained in the cycloaddition reaction. Re-
placement of the diethanolamine with pinanediol confir-
med that the pure enantiomers could be isolated. The
TADDOL could also be readily recovered in \90%
yield and reused. Further studies are currently under-
way in our laboratories including the application of the
these optically active boronic ester substituted D2-isoxa-
zolines to the synthesis of natural products and biolog-
ically important molecules.
the diastereoselectivity of the cycloaddition reaction
was easily carried out by 1H-NMR analysis of the crude
exchange reaction mixture. A variety of TADDOLs
(10a–e) [11a] were explored in this reaction and the
selectivities obtained are shown Table 1 below. At-
tempts to increase the selectivity of these cycloadditions
by changing solvent or temperature of the reaction did
not have any significant impact on the selectivity.
In connection with a synthetic project being carried
out in our laboratories, we wanted to explore the use of
a-substituted optically active vinylboronic esters in this
reaction. Two of the a-substituted vinylboronic esters
explored in this reaction were 11 and 12.
2. Experimental
Unless otherwise noted, materials were obtained
from commercial suppliers and were used without fur-
ther purification. Trimethyl borate and tri-isopropyl
borate were freshly distilled prior to use. Tetrahydro-
furan (THF) and diethyl ether were freshly distilled
from sodium/benzophenone ketyl under nitrogen. High
resolution mass spectra (HRMS) were obtained on a
When the reaction of benzonitrile oxide (6) was carried
out with 11 and 12 we were delighted to find much
higher levels of asymmetric induction than were ob-
served with the unsubstituted vinylboronic esters. The
selectivities in these reactions were also determined by
exchange of the TADDOL with pinanediol and 1H-
NMR analysis. Vinylboronic ester 11 afforded an 8:1
mixture of diastereomers and boronic ester 12 gave a
5:1 mixture of diastereomers. The increased level of
asymmetric induction displayed by 11 and 12 is cur-
rently under further investigation.
1
AG Autospec GC/MS spectrometer. H-NMR spectra
were measured in CDCl3 on a Bruker AM 360 spec-
trometer (360 MHz) or a Hitachi RS-1200 (60 MHz).
13C-NMR spectra were recorded in CDCl3 at 90.0 MHz
(Bruker AM 360), unless otherwise specified. 11B-NMR
spectra were measured in CDCl3 on a Bruker AM 360
spectrometer and BF3·Et2O was used as a reference.
2.1. Pinanediol 6inylboronic ester (5)
Separation of the mixture of diastereomers obtained
from these cycloadditions proved to be difficult by
normal methods. At this point we decided to explore
the possibility of carrying out the cycloaddition, ex-
changing the TADDOL for diethanolamine, and re-
A solution of (+)-pinanediol (518 mg, 3.04 mmol)
and dibutyl vinylboronic ester (560 mg, 3.04 mmol) in
pentane/ether (10:1) (10 ml) was stirred at room tem-
perature (r.t.) for 6 h. The solvent was removed under
reduced pressure and the residue was purified by Kugel-
rohr distillation (61°C, 0.1 mmHg) to afford the
product as a clear oil (604 mg, 98%). 1H-NMR (360 Hz,
CDCl3) l 6.15 (dd, J=19.4, 4.3 Hz, 1H), 6.04 (dd,
J=13.6, 4.3 Hz, 1H), 5.90 (dd, J=19.4, 13.6 Hz, 1H),
4.31 (dd, J=8.9, 1.9 Hz, 1H), 2.37–2.33 (m, 1H),
2.27–2.21 (m, 1H), 2.15–2.10 (m, 1H), 1.95–1.90 (m,
2H), 1.41(s, 3H), 1.31 (s, 3H), 1.15 (d, J=10.9 Hz, 1H),
0.88 (s, 3H).
Table 1
Cycloaddition reaction selectivities of TADDOLs
2.2. Cycloaddition product from reaction of 5 with 6
TADDOL
Nitrile oxide
Ratio of diastereomers
A solution of pinanediol vinylboronic ester (5) (418
mg, 2.03 mmol) and phenylhydroximic acid chloride in
THF (20 ml) was cooled to −78°C. Et3N (207 mg, 2.05
mmol) in THF (5 ml) was added dropwise to the
mixture at −78°C. After 12 h, the reaction was al-
lowed to warm to r.t. The triethylamine hydrochloride
salt was removed by filtration and the filtrate was
10a
10b
10b
10c
10d
10e
PhCNO
PhCNO
t-BuCNO
PhCNO
PhCNO
PhCNO
2.8:1
3:1
2.5:1
2.2:1
2.5:1
2.8:1

90
R.H. Wallace, K.K. Zong / Journal of Organometallic Chemistry 581 (1999) 87–91
concentrated under reduced pressure. The residue was
purified by Kugelrohr distillation (135°C, 0.05 mmHg)
to afford a pale yellow oil (94%). IR (neat) 3005, 2980,
1570, 1450 cm−1. 1H-NMR (360 MHz, CDCl3) l 7.75–
7.68 (m, 2H), 7.42–7.37 (m, 3H), 4.42–4.38 (m, 1H),
3.54–3.50 (m, 1H), 3.38–3.30 (m, 1H), 2.38–2.35 (m,
1H), 2.27–2.24 (m, 1H), 2.13–2.09 (m, 1H), 1.93–1.90
(m, 1H), 1.45 (s, 3H), 1.30 (s, 3H), 1.17–1.13 (m, 1H),
0.86 (s, 3H). 13C-NMR (90 MHz, CDCl3) 156.5, 129.9,
129.6, 128.5, 126.8, 86.9, 78.6, 68.1, 51.8, 39.3, 38.2,
38.1, 35.0’28.4, 26.9, 26.3, 23.8. MS m/z 55 (79), 67
(56), 77 (100), 104 (79), 137 (59), 153 (58), 174 (57), 325
(29). HRMS Calc. for Cl19H24BNO3, 325.184. Found
325.184.
2.5. General procedure for the preparation of the
TADDOL substituted 6inylboronic esters
A
solution of TADDOL (0.99 mmol) and
ethyleneboronic anhydride pyridine complex (80 mg,
0.33 mmol) in toluene (10 ml) was placed in a 50 ml
round bottom flask and fitted with Dean–Stark ap-
paratus. The reaction was refluxed for 2 h, while the
water/toluene azeotrope was trapped. After the reaction
was cooled to r.t., the residue was further concentrated
in vacuo (0.1 mmHg) to afford the vinyl–TADDOL–
boronate (9).
2.6. Preparation of 11 and 12
A
solution of the corresponding dibutyl vinyl
2.3. Vinylboronic anhydride–pyridine complex
boronate (1.55 mmol) and TADDOL (1.55 mmol) in
xylene was refluxed for 2 h while the n-butanol/xylene
azeotrope was trapped. The residue was concentrated in
vacuo (0.1 mmHg) to afford the product. The product
was used in the next reaction without further
purification.
A stirred suspension of dibutyl vinylboronate (15.0 g,
82.0 mmol), phenothiazine (0.80 g, 0.40 mmol) and
water (40 ml) was distilled (ca. 55°C, 20 mmHg)
through a 30 cm vigreux column until the butanol/wa-
ter azeotrope and the majority of the water was re-
moved to leave a moist residue. The residue of
ethyleneboronic acid was treated with pyridine (30 ml)
and stirred for 12 h. The water/pyridine azeotrope was
distilled off (ca. 55°C, 20 mmHg) by a similar proce-
dure above and the residue was purified by Kugelrohr
distillation to afford a white solid (5.8 g, 88%). M.p.
49–52°C. 1H-NMR (360 MHz, CDCl3) l 8.89–8.85
(m, 2H, pyr), 8.04–8.00 (m, 1H, pyr), 7.65–7.60 (m,
2H, pyr), 6.06–5.98 (m, 6H), 5.87–5.76 (m, 3H). 13C-
NMR (90 MHz, CDCl3) d 143.9, 140.6, 138.0, 131.3,
125.3.
2.7. Di-n-butyl-(2-propenyl)-boronate
This compound has been prepared previously by
Matteson [13] by a slightly different method. To a
solution of freshly distilled trimethyl borate (8.73 g,
0.084 mol) in distilled THF (100 ml) was added drop-
wise 2-propenylmagnesium bromide (2.2 M, 0.084 mol)
at −78°C. The mixture was allowed to warm to r.t.
over 2 h and then cooled to −78°C. Water (10 ml) and
phenothiazine (0.03 g) were added and the addition of
3 M HCI (50 ml) followed. The mixture was allowed to
warm to 0°C and stirred for 3 h. After all solid materi-
als were dissolved, the two phases were separated. The
aqueous phase was extracted with n-butanol (25 ml×
3) and the combined organic phases was washed with
brine (20 ml×3), then saturated sodium bicarbonate.
The n-butanol/water azeotrope was first distilled off
under reduced pressure and the residue was fractionally
distilled under reduced pressure (3–4 mmHg, 83–86°C)
to afford the product as a clear oil (12.4 g, 74%).
1H-NMR (360 MHz, CDCl3) l 5.56 (s, 1H), 5.26 (s,
1H), 3.90–3.88 (m, 4H), 1.82 (s, 3H), 1.5–1.53 (m, 4H),
1.37-1.34 (m, 4H), 0.93–0.90 (m, 6H). 13C-NMR (90
MHz, CDCl3) l 128.65, 124.16, 63.84, 33.84, 22.62,
18.98, 13.83.
2.4. Bis(dimethylamino)6inyl borane (7)
A
solution of freshly distilled bis(dimethyl-
amino)chloroborane (44.1 g, 0.328 mol) in distilled
Et2O/pentane (200 ml, 1:1 ratio) was cooled to
−78°C with stirring. Vinylmagnesium chloride (1.5 M
in THF, 219 ml, 0.328 mol) was added drop-wise
over 2 h and the mixture was slowly warmed to 0°C
and stirred for a further 12 h. The solid was removed
through moisture protected filtering. The volatiles
were distilled at atmospheric pressure and the residue
was fractionally distilled under reduced pressure
(52–53°C, 29–30 mmHg) to afford the product as
a clear oil (38.0 g, 92%). Since the compound is ex-
tremely moisture sensitive, special care should be taken
2.8. Di-n-butyl-(a-styrenyl)-boronate
1
during distillation. H-NMR (360 MHz, CDCl3) l 6.01
This compound has been prepared previously by
Matteson [13] and coworkers by a slightly different
method. This compound was prepared by a similar
procedure to that described above. The crude product
was purified by Kugelrohr distillation (85–90°C, 0.1
(dd, J=20.0, 14.0 Hz, 1H), 5.73 (dd, J=14.0, 4.3 Hz,
1H), 5.48 (dd, J=20.0, 4.3 Hz, 1H), 2.70 (s, 12 H).
13C-NMR (90 MHz, CDCl3) l 138.2 (br, C–B), 128.5,
40.5.

R.H. Wallace, K.K. Zong / Journal of Organometallic Chemistry 581 (1999) 87–91
91
mmHg) to afford the product as a clear oil (80%).
1H-NMR (360 MHz, CDCl3) l 7.41–7.20 (m, 5H), 5.93
(d, J=1.7 Hz, 1H), 5.49 (d, J=1.7 Hz, 1H), 3.85–3.82
(m, 4H), 1.55–1.54 (m, 4H), 1.35–1.32 (m, 4H), 0.91–
0.89 (m, 6H). 13C-NMR (90 MHz, CDCl3) l 141.50,
128.48, 127.49, 127.15, 126.34, 122.41, 64.27, 33.70,
18.95, 13.80.
2H), 1.46 (s, 3H), 1.40 (s, 3H), 1.30 (s, 3H), 1.15 (d,
J=10.9 Hz, 1H), 0.85 (s, 3H). 13C-NMR (90 MHz,
CDCl3) l 155.22, 130.11, 129.67, 128.55, 126.18, 86.98,
78.74, 51.18, 44.69, 39.34, 38.18, 35.21, 35.19, 30.19,
28.44, 27.00, 26.39, 23.93, 23.73, 23.68.
Acknowledgements
2.9. Preparation of cycloadducts from 11
We would like to thank the Research Grants Com-
mittee of The University of Alabama, Armstrong At-
lantic State University (AASU), and The Research and
Scholarship Grants Committee of AASU for support-
ing this work. We would also like to thank Chuck
Rawlinson for assistance in obtaining specific rotation
data.
A solution of 11 (974 mg, 1.55 mmol) and phenylhy-
droximic acid chloride (313 mg, 2.01 mmol) in freshly
distilled THF (15 ml) was cooled to 0°C. Triethylamine
(203 mg, 2.01 mmol) in THF (5 ml) was added drop-
wise over 30 min and stirred for 2 h. A white solid
(triethylamine hydrochloride) was filtered through a
glass frit under pressure (argon) and the filtrate was
used in the next reaction.
2.10. Cycloadduct–diethanolamine complex
References
[1] (a) D.P. Curran, in: C.T. Greenwich, D.P. Curran (Eds.), Ad-
vances in Cycloaddition, vol. 1, JAI Press, Greenwich, CT, p.
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Isoxazoles Part I, Wiley, New York, 1991, p. 417. (c) P.
Caramella, P. Grunanger, in: A. Padwa (Ed.), 1,3-Dipolar Cy-
cloaddition Chemistry, vol. 1, Wiley-Interscience, 1984, p. 291.
(d) A.P. Kozikowski, Acc. Chem. Res. 17 (1984) 410. (e) V.
Jager, I. Muller, Tetrahedron 41 (1985) 3519.
[2] (a) D.S. Matteson, Tetrahedron 45 (1989) 1859. (b) A. Pelter, K.
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York, 1988. (c) M.V. Rangaishenvi, B. Singaram, H.C. Brown,
Org. Chem. 56 (1991) 3286.
[3] (a) K.M. Sadhu, D.S. Matteson, Organometallics 4 (1985) 1687.
(b) T.J. Michnick, D.S. Matteson, Synlett. (1991) 631. (c) H.C.
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(1966) 598. (b) G. Bianchi, A. Cogoli, P. Grunanger, Ric. Sci.
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[5] (a) R.H. Wallace, K.K. Zong, M.P. Schoene, Current Topics in
The Chemistry of Boron, Special Publication of the Royal
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R.H. Wallace, M. Gotz, M. McCutchen, in preparation.
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[8] R.H. Wallace, Y. Lu, J. Liu, J. Atwood, Synlett. (1992) 992.
[9] D.S. Matteson, J. Am. Chem. Soc. 82 (1960) 4228.
[10] K. Marasasaka, Synthesis (1991) 1.
[11] (a) A.K. Beck, B. Bastani, D.A. Plattner, W. Petter, D. Seebach,
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16 (1969) 33.
The solution above was treated with diethanolamine
(210 mg, 2.0 mmol) at r.t. White solids began to form
within 30 min. The reaction was stirred for 3 h and the
solid was collected by vacuum filtration (ca. 85%). The
product was pure enough for analytical purposes. The
optically pure cycloadduct was obtained from recrystal-
lization in acetone or toluene. M.p. 206–210°C. 1H-
NMR (360 MHz, CDCl3) l 7.61–7.55 (m, 2H),
7.45–7.31 (m, 3H), 6.11 (s, 1H), 4.15–3.89 (m, 4H),
3.58–3.38 (m, 3H), 3.02–2.81 (m, 3H), 1.22 (s, 3H).
13C-NMR (90 MHz, CDCl3) l 157.12, 130.50, 129.51,
128.52, 126.53, 63.38, 63.19, 52.27, 52.16, 44.47, 23.82
2.11. Phenyl-5,5-methyl-pinanylboronat-Z2-isoxazoline
To a suspension of the diethanolamine complex
above (363 mg, 1.40 mmol) and (+)-pinanediol (238
mg, 1.40 mmol) in Et2O (6 ml) was added 4–5 drops of
6 M HCl at r.t. As the reaction proceeded, it became
clear. The mixture was stirred for 3 h and the organic
layer was vacuum-filtered through a short column
packed with MgSO4. The filtrate was concentrated un-
der reduced pressure and further concentrated by vac-
uum pump (0.05 mmHg) to afford the product as a
clear oil (455 mg, 100%). [h]2D0= +10.63° (c=1.3,
1
CH2Cl2). B.p. 119–121°C (0.05 mmHg). H-NMR (360
MHz, CDCl3) l 7.75–7.65 (m, 2H), 7.45–7.35 (m, 3H),
4.41 (dd, J=8.8, 1.7 Hz, 1H), 3.52 (d, J=16.2 Hz,
1H), 3.06 (d, J=16.2 Hz, 1H), 2.41–2.30 (m, 1H),
2.29–2.25 (m, 1H), 2.13–2.10 (m, 1H), 1.95–1.93 (m,
.