Synthesis of a (β-acetamido-α-acetoxyethyl)boronic ester via azido boronic esters

Article abstract of DOI:10.1016/j.jorganchem.2008.03.031

(Azidomethyl)boronic esters of 1,2-dicyclohexyl-1,2-ethanediol ( DICHED ) and pinanediol have been prepared from the corresponding (bromomethyl)boronic esters. Conversion to (2-azido-1-chloro- or bromoethyl)boronic esters by reaction with a (dihalomethyl)lithium followed. Attempted displacement of halide from DICHED (2-azido-1-haloethyl)boronates with alkoxides failed. Reaction of either pinanediol or DICHED (2-azido-1-chloromethyl)boronate with sodium acetate in acetic acid yielded the 1-acetoxy derivative as a ～1:1 mixture of diastereomers, indicating probable involvement of an α-boryl carbocation intermediate. Hydrogenation of the pinanediol azido boronic ester over platinum in a solution of hydrogen chloride in dioxane was accompanied by deacetylation to form the impure (2-amino-1-hydroxyethyl)boronic ester hydrochloride. Attempted purification of this material resulted in deboronation to ethanolamine. Acetylation yielded pinanediol (2-acetamido-1-acetoxyethyl)boronate.

Full text of DOI:10.1016/j.jorganchem.2008.03.031

Journal of Organometallic Chemistry 693 (2008) 2258–2262
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Journal of Organometallic Chemistry
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Synthesis of a (b-acetamido-a-acetoxyethyl)boronic ester via azido boronic esters
*
Donald S. Matteson , Davis Maliakal, Levente Fabry-Asztalos
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
(Azidomethyl)boronic esters of 1,2-dicyclohexyl-1,2-ethanediol (‘‘DICHED”) and pinanediol have been
prepared from the corresponding (bromomethyl)boronic esters. Conversion to (2-azido-1-chloro- or
bromoethyl)boronic esters by reaction with a (dihalomethyl)lithium followed. Attempted displacement
of halide from DICHED (2-azido-1-haloethyl)boronates with alkoxides failed. Reaction of either pinane-
diol or DICHED (2-azido-1-chloromethyl)boronate with sodium acetate in acetic acid yielded the 1-acet-
oxy derivative as a ꢀ1:1 mixture of diastereomers, indicating probable involvement of an a-boryl
carbocation intermediate. Hydrogenation of the pinanediol azido boronic ester over platinum in a solu-
tion of hydrogen chloride in dioxane was accompanied by deacetylation to form the impure (2-amino-1-
hydroxyethyl)boronic ester hydrochloride. Attempted purification of this material resulted in deborona-
tion to ethanolamine. Acetylation yielded pinanediol (2-acetamido-1-acetoxyethyl)boronate.
Ó 2008 Elsevier B.V. All rights reserved.
Received 12 January 2008
Received in revised form 31 March 2008
Accepted 31 March 2008
Available online 7 April 2008
Keywords:
Azide
Boronic ester
Homologation
Boryl carbocation
Acetoxy boronic ester
Amino boronic ester
1. Introduction
a-Heteroatom substituted (b-aminoalkyl)boronic acid deriva-
tives have proved unusually difficult to make. The synthesis of
Boronic acids bearing functional substituents are of interest as
analogs of biologically significant carboxylic acids [1,2]. The most
noteworthy example to date is the successful proteasome inhibitor
bortezomib (VelcadeTM, Millennium Pharmaceuticals) [3], an a-ami-
do boronic acid that has been approved for treatment of relapsed
multiple myeloma and mantle cell lymphoma in the United States
and numerous other countries. The functionalized boronic acids
2-amino-6-boronohexanoic acid [4] and S-[2-boronoethyl]cysteine
[5] have received recent attention as arginase inhibitors capable of
increasing biological nitric oxide levels.
silylated (2-amino-1-chloroethyl)boronic esters from silylated
aminomethyl boronic esters has been described [11]. The 1-chlo-
ride was displaced by sodio(methanethiol), and desilylation and
treatment with trimethylsilyl isocyanate led to the [2-ureido-1-
(methylthio)ethyl]boronic ester [11]. It appeared that dimethyl-
amino substitution was also successful, though the product was
not completely purified. Attempts to displace the chloride with
benzyl oxide failed [11]. Attempted insertions of (dichlorometh-
yl)lithium into silylated a-benzylamino- or a-formamido-b-trityl-
oxy boronic esters failed [11].
Syntheses of the foregoing examples involved introduction of
amine functionality into boronic esters, which for remote amino
groups was easy [4,5] and for a-amido boronic esters [2,3] was a
difficult problem that was solved some time ago [6]. b-amino
boronic esters pose some synthetic problems and have received
much less attention. Soon after the discovery of b-halo boronic es-
ters, replacement of the b-halide by nitrogen nucleophiles was
shown not to be a possibility because of rapid base catalyzed elim-
ination of boron and halogen [7]. Butler and Soloway made (2-ure-
idoethyl)boronic acid via hydroboration of vinylurea in 1965 [8]. A
boronic acid analog of aspartic acid, b-(dihydroxyboryl)alanine, has
been made from a (halomethyl)boronic ester via an amidomalonic
ester synthesis [9] or from a b-lithiated Boc-protected amine [10].
These routes are not suitable for making b-amino boronic esters
bearing a-heteroatom substituents.
The failure of the alkoxide substitution was unexpected,
though a previous failure of alkoxide substitution has been ob-
served with an a-chloroallylboronic ester [12], even though sily-
lated amino substitution on the same compound proceeded
normally [13]. a-Azido boronic esters have been homologated
with (chloromethyl)lithium to provide asymmetric syntheses of
a-amino alcohols [14], a-amino acids [15], and an a-cyanometh-
yl-b-azido-c-silyloxy boronic ester [16]. This study was begun in
the hope that the b-azido substituent also might not interfere with
a-chloride replacement by alkoxide and thus might provide (a-
alkoxy-b-azidoalkyl)boronic esters as potentially useful synthetic
intermediates.
2. Results
(R,R)-1,2-Dicyclohexyl-1,2-ethanediol (‘‘DICHED”) (bromo-
methyl)boronate (1) (ee >99%) [17] was converted to the (azido-
methyl)boronate (2) in nearly quantitative yields according to
* Corresponding author. Tel.: +1 509 335 3365; fax: +1 509 335 8867.
E-mail address: dmatteson@wsu.edu (D.S. Matteson).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.03.031

D.S. Matteson et al. / Journal of Organometallic Chemistry 693 (2008) 2258–2262
2259
previously optimized phase-transfer conditions for reactions of
a-halo boronic esters with sodium azide catalyzed by tetrabutyl-
ammonium bromide in water/ethyl acetate [16]. There being no
need to keep the reaction temperature low to preserve stereoselec-
tion in the absence of a stereocenter at the reactive site, it was con-
venient to heat the mixture to reflux and shorten the reaction time
to a few hours. Homologation of 2 with (dihalomethyl)lithium in
the usual manner [14] provided DICHED (1-chloro-2-azidoeth-
yl)boronate (3a) (76%) or its bromo analogue (3b) (64%) as nearly
pure single diastereomers.
matched an authentic sample of 12 prepared from aqueous ethanol-
amine and hydrochloric acid with sodium tetraphenylborate.
Although the preparations of the 2-azido-1-haloethylboronic
esters 3 proceeded efficiently, the next anticipated step failed to-
tally. Reactions of 3a or 3b with lithium or sodium benzyl oxide,
sodium methoxide or p-methoxybenzyl oxide, or lithium phenox-
ide failed to yield any substitution product and resulted in
deboronation to DICHED alkoxyborate (4), presumably with b-
elimination of azide.
3. Discussion
Although the results of this study are disappointing from a
synthetic point of view, they do reveal significant information
about the behavior of this highly functionalized series of boronic
esters.
One other possibility for introducing an a-oxy substituent in
the presence of a b-azido substituent remained. Displacement
of halide from an a-halo boronic ester by sodium acetate in
hot acetic acid had been reported in 1963 [18]. Because (+)-
pinanediol (from (+)-a-pinene) is easier to make than DICHED
and its boronic esters are even more resistant to hydrolysis, test-
ing of this pathway was carried out with pinanediol esters. (+)-
Pinanediol (bromomethyl)boronate (5) (ee ꢀ99%) [19] was
converted to the azido derivative 6 and on to pinanediol (1-
chloro-2-azidoethyl)boronate (7) in the same manner as 1 was
converted to 3a. Reaction of 7 with sodium acetate in acetic acid
did not proceed appreciably in 24 h at room temperature, but
when heated overnight at ꢀ90 °C produced a mixture of diaste-
reomers 9 in a ratio between 2:3 and 1:1 in high yield. The a-
boryl carbocation 8 is postulated to be an intermediate. The
(S,S)-DICHED boronic ester ent-3a was also tested with sodium
acetate in acetic acid. Again, after 24 h at 20-25 °C the starting
material was unchanged except for a barely detectable acetyl
CH3 peak in the 1H NMR. On heating at 95 °C for 20 h, conversion
to a 1:1 mixture of diastereomeric acetates was nearly quantita-
tive. This was further confirmed by transesterification of the
DICHED ester mixture with (+)- and (ꢁ)-pinanediol, each of
which yielded a 1:1 mixture of diastereomers having the same
appearance in the 1H NMR spectrum.
Pinanediol (1-acetoxy-2-azidoethyl)boronate (9) was hydroge-
nated at 10 atmospheres over platinum in dioxane in the presence
of hydrogen chloride. Unfortunately, hydrogenation under these
acidic conditions was accompanied by deacetylation to the a-hydro-
xy boronic ester 10, which proved unstable on attempted
purification. Prompt acetylation of 10 led to pinanediol 1-acetoxy-
2-acetamidoethylboronate (11). When the hydrogenation was car-
ried out in methanol, deboronation of 10 occurred and the product
isolated on treatment with aqueous sodium tetraphenylborate was
ethanolamine tetraphenylborate (12), which showed a characteris-
tic pair of triplets in the 1H NMR at d 2.88 and 3.66, J = 5.3 Hz, and
The lack of stereoselectivity in the reaction of the pinanediol
2-azido-1-chloroethylboronate (7) or the corresponding (S,S)-
DICHED ester ent-3a with sodium acetate in acetic acid strongly
implies that this displacement occurs via a carbocation (SN1) path-
way. The rationale for testing ent-3a was that previous studies of
solvolytic substitution or elimination reactions of a-halo boronic
esters have indicated that these reactions proceed with consider-
able nucleophilic assistance by the solvent [7], and that reactions
involving coordination of a nucleophile to boron bound to a
C2-symmetrical diol can result in a high degree of kinetic resolu-
tion [20]. Although the hypothesis that the lack of stereoselection
could result from epimerization of 7 or ent-3a prior to substitution
has not been rigorously ruled out, it seems unlikely that acetate
could displace chloride where alkoxide fails, and unlikely that
there would be no kinetic differentiation between ent-3a and its
epimer in a substitution process. The total lack of stereoselection
in the sodium acetate reactions implies that the chiral diol units
are too far from the substitution site to interact sterically, and that
assistance by the boron atom in the acetate connection process
must be negligible.
The instability of the a-hydroxy boronic ester 10 was not antic-
ipated, inasmuch as other a-hydroxy boronic esters have been gen-
erated as intermediates by cleavage of benzylic ethers and
converted to stable derivatives [16,21], though isolation has not
been attempted. Instability of a-hydroxy boronic esters in basic
solution is a possible but unproved explanation for the high yields
of 1-hexanol obtained from hydroboration of 1-hexyne followed
by alkaline oxidation with hydrogen peroxide [22,23]. The well
documented instability of a-amino boronic esters in their free
amine form [6] implies very strongly that deprotonated a-hydroxy
boronic esters would rearrange rapidly to the corresponding trialk-
oxyboranes. Hydrolysis of methylboronic acid to methane and bo-
ric acid, CH3B(OH)2 + H2O = CH4 + B(OH)3, is exothermic by an

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D.S. Matteson et al. / Journal of Organometallic Chemistry 693 (2008) 2258–2262
estimated 112.4 kJ/mol (26.9 kcal/mol) [24]. The alcoholysis or
hydrolysis of an a-hydroxy boronic ester to an alcohol and borate
ester or boric acid should be similarly exothermic, and the pres-
ence of the a-hydroxy or alkoxide group evidently provides a path-
way for hydrolysis that does not exist for simple alkylboron
compounds.
nium chloride to ensure removal of tetrabutylammonium salts.
Concentrated under reduced pressure yielded crystalline
2
(7.66 g, 87%); IR 2099 cmꢁ1 (N3); 300 MHz 1H NMR (C6D6) d
0.85–1.76 (m, 22H), 2.70 (ab, J = 17.4 Hz, J = 21.3 Hz, 2H), 3.71 (dia-
stereotopic pair, 0.013 d separation, 2H); 75 MHz 13C NMR (CDCl3)
d
C
25.9, 26.1, 26.5, 27.4, 28.5, 42.9, 84.3. HRMS Calc. for
15H26BN3O2: 291.2118. Found: 291.2123%. Flash chromatography
Alkoxides are the only common nucleophiles that fail to dis-
place chloride from certain a-chloro boronic esters, including
b-azido boronic esters, as noted above [11–15]. The exothermic
character of reactions that replace B–C bonds by B–O bonds [24]
is undoubtedly a major factor in some cases. Alkoxide displace-
ments fail when there is another pathway accessible for the
decomposition of the (a-chloroalkyl)(trialkoxy)borate intermedi-
ate, b-elimination in the case of the azido compounds and perhaps
dissociation to an a-chloroallylic anion in the case of certain
a-chloro boronic esters [12]. The reason for failure of silylated
b-amino boronic esters to undergo a-chloro displacement by alk-
oxide was not clear [11]. In retrospect, it appears all the more
remarkable that b-elimination of boron and oxygen from (b-alk-
oxy-a-chloroalkyl)(trialkoxy)borates was not evident in the assem-
bly of a sequence of four adjacent benzyloxy substituted carbons
for an asymmetric synthesis of ribose [25], though it could have
been an unrecognized factor in the inefficiency of the process for
introducing a fifth carbon in the same manner.
on silica (Rf 0.76, 30% diethyl ether in petroleum ether) provided
further purification of 2.
5.3. [2(1S),4R,5R]-4,5-Dicyclohexyl-2-(1-chloro-2-azidoethyl)-1,3,2-
dioxaborolane (3a)
Butyllithium (1.6 M in hexanes, 13.4 mL, 21.5 mmol) was added
to a solution of dichloromethane (4.15 mL, 64.4 mmol) in THF
(60 mL) stirred under argon at ꢁ100 °C to generate (dichlorometh-
yl)lithium. After 5 min (4R,5R)-4,5-dicyclohexyl-2-(azidomethyl)-
1,3,2-dioxaborolane (2) (5.00 g, 17.17 mmol) in THF (5 mL) was
added via cannula. Anhydrous powdered zinc dichloride (4.68 g,
34.34 mmol) was added. The bath temperature was allowed to rise
to 20–25 °C and the mixture was stirred for 48 h. After concentra-
tion under reduced pressure, diethyl ether (30 mL) was added. The
ether solution was washed three times with ammonium chloride
solution and the ether phase was dried over anhydrous magnesium
sulfate and filtered. Concentration yielded clear, viscous liquid 3a
(4.40 g, 76%); IR 2102 cmꢁ1 (N3); 300 MHz 1H NMR (C6D6) d
0.84–1.79 (m, 22H), 3.26 (m, 2H), 3.39 (m, 1H), 3.80 (d, J = 5.4 Hz,
2H); 300 MHz 1H NMR (CDCl3) d 0.8–1.9 (m), 3.6–3.7 (m, 3H),
3.90 (m, 2H); 75 MHz 13C NMR (C6D6) d 26.4, 26.5, 26.9, 27.7,
28.7, 41.6 (broad, C-B), 43.3, 54.8, 84.5. HRMS Calc. for
4. Conclusions
(1) Attempted replacement of chloride from (1-halo-2-azido-
ethyl)boronic esters with alkoxide nucleophiles is superseded by
b-elimination of boron and azide. (2) Replacement of chloride from
a-chloro boronic esters by acetate in acetic acid apparently pro-
ceeds via a carbocation mechanism. (3) Chiral direction by the
1,2-dicyclohexyl-1,2-ethanediol boronic ester group does not ex-
tend to nucleophilic attack on an a-boryl carbocation site. (4) Cat-
alytic hydrogenation of a (1-acetoxy-2-azidoethyl)boronic ester in
acid yields a (1-hydroxy-2-aminoethyl) boronic ester salt that is
highly susceptible to protodeboronation. Other methods of reduc-
tion that might preserve the acetoxy group have not been exten-
sively explored. (5) a-Acetoxy boronic esters can be generated
efficiently as gross diastereomeric mixtures, separable in principle,
but no diastereoselective route has been found.
C
16H27BClN3O2 (M+-N2): 311.1823. Found: 311.1820%. No evidence
for the diastereomer of 3a was observed, though it might not have
been noticed at the 1–2% level.
5.4. [2(1S),4R,5R]-4,5-Dicyclohexyl-2-(1-bromo-2-azidoethyl)-1,3, 2-
dioxaborolane (3b)
To
a solution of (4R,5R)-4,5-dicyclohexyl-2-(azidomethyl)-
1,3,2-dioxaborolane (2) (2.96 g, 10.16 mmol) in THF (70 mL) was
added dibromomethane (2.13 mL, 30.49 mmol). The mixture
was cooled to ꢁ78 °C and lithium diisopropylamide (1.5 M in
cyclohexane, 10.16 mL, 15.24 mmol) was added dropwise. After
5 min, zinc dichloride (1.0 M in diethyl ether, 45.7 mL) was
added. The bath temperature was allowed to rise to 20–25 °C
and the reaction mixture was stirred under inert atmosphere
for 24 h. Solvents were removed under reduced pressure and
diethyl ether was added (30 mL). The diethyl ether solution was
washed three times with ammonium chloride solution and the
ether phase was dried over anhydrous magnesium sulfate and fil-
tered. Concentration at reduced pressure yielded yellow, viscous
liquid 3b (1.77 g, 64%); 300 MHz 1H NMR (CDCl3) d 0.97–1.78
(m, 22H), 3.42 (m, 1H), 3.72 (m, 2H), 3.98 (d, J = 5.1 Hz, 2H).
5. Experimental
5.1. (4R,5R)-4,5-Dicyclohexyl-2-(bromomethyl)-1,3,2-dioxaborolane
(1)
Diisopropyl (bromomethyl) boronate (37.27 g, 0.167 mol) [17]
was stirred for 15 h with (R,R)-1,2-dicyclohex-1,2-ethanediol
(37.84 g, 0.167 mol) [26] in diethyl ether (150 mL) at 20-25 °C.
Concentration at reduced pressure yielded white crystalline 1
(50.79 g, 92%); 300 MHz 1H NMR (C6D6) d 0.88–1.79 (m, 22H),
2.60 (s, 2H), 3.94 (d, 2H, J = 5.1 Hz); 75 MHz 13C NMR (C6D6) d
26.2, 26.3, 26.7, 27.5, 28.6, 43.2, 84.3.
HRMS Calc. for
357.1290%.
C
16H27BBrN3O2 (M+-N2): 357.1298. Found:
5.5. Attempted displacements of chloride from [2(1S),4R,5R]-4,5-
dicyclohexyl-2-(1-chloro-2-azidoethyl)-1,3,2-dioxaborolane 3a by
alkoxides
5.2. (4R,5R)-4,5-Dicyclohexyl-2-(azidomethyl)-1,3,2-dioxaborolane
(2)
A solution of (4R,5R)-4,5-dicyclohexyl-2-(bromomethyl)-1,3,2-
dioxaborolane (1) (10.00 g, 0.304 mol) in ethyl acetate (50 mL)
was stirred with a solution of sodium azide (59.25 g, 0.91 mol)
and tetrabutylammonium bromide (4.89 g, 15.19 mmol) in water
(150 mL) under argon at 20–25 °C for 48 h. The ethyl acetate phase
was concentrated and a solution of the residue in a mixture of
ether and pentane was extracted repeatedly with aqueous ammo-
Several attempts to displace chloride from 3 by various alkox-
ides led to mixtures of unchanged 3 and what appeared to be
[2(1S),4R,5R]-4,5-dicyclohexyl-2-alkoxy-1,3,2-dioxaborolane (4)
or its hydrolysis products, with loss of the azido group and
the CH2CHCl fragment. Sodium p-methoxybenzyl oxide [from
p-methoxybenzyl alcohol (3.2 mmol) in anhydrous DMSO (di-
methyl sulfoxide) (35 mL) and sodium hydride (3.1 mmol) 24 h]

D.S. Matteson et al. / Journal of Organometallic Chemistry 693 (2008) 2258–2262
2261
with 3a (3 mmol) in DMSO (12 mL) at 20–25 °C for 24 h resulted in
partial decomposition of 3a to 4 (R = p-methoxybenzyl) as indi-
cated by 300 MHz 1H NMR, 75 MHz 13C NMR, and IR spectra. Lith-
ium benzyl oxide [from benzyl alcohol (9.4 mmol) in THF (65 mL)
and butyllithium (8.6 mmol) at ꢁ78 °C] with 3a (7.8 mmol) in THF
(10 mL) 24 h at 20–25 °C led to a mixture of unchanged 3a, benzyl
alcohol, free DICHED, and unknown minor byproducts by 1H NMR
analysis, and the azide peak in the IR was diminished in intensity.
Inclusion of an equivalent of DMSO or running the reaction in
DMSO as solvent did not change the result. Similar partial decom-
position was seen with lithium or sodium phenoxide in THF or
DMSO and 3a. Lithium methoxide in THF at 40 °C for 24 h yielded
no substitution product.
reomer of 7 was observed, though it might not have been noticed
at the 1–2% level.
5.9. Pinanediol (1-acetoxy-2-azidoethyl)boronate (9)
1-Chloro-2-azidoethyl pinanediol boronate (7) (1 g, 3.53
mmol) was heated in glacial acetic acid (35 mL) with sodium ace-
tate (2.89 g, 35.3 mmol) for 12 h at 100–110 °C. After the reaction,
acetic acid was distilled, diethyl ether (200 mL) was added to the
residue, and the remaining acid was neutralized with saturated
sodium bicarbonate solution. Extracted with ether (3 ꢂ 50 mL)
and washed with water (2 ꢂ 50 mL). The combined organic layer
was evaporated off and the residue on flash column chromatogra-
phy using 5% ether in pentane as eluant afforded 1-acetoxy-2-azi-
doethyl pinanediol boronate 9 as a colorless liquid (977 mg, 90%).
5.6. Attempted reduction of the azide group of b-azido-a-chloro
boronic ester 3a
IR (neat): 2925, 2100, 1733, 1376, 1288, 1244 cmꢁ1 1H NMR: d
;
4.32 (m, 4H), 3.58 (m, 4H), 2.28 (m, 4H), 2.138 (s, 3H), 2.135 (s,
3H), 2.05 (m, 2H), 1.88 (m, 4H), 1.41 (s, 3H), 1.39 (s, 3H), 1.29
(s, 6H), 1.25 (d, J = 11.1 Hz, 1H), 1.23 (d, J = 10.8 Hz, 1H), 0.84 (s,
6H); 13C NMR: d 171.92, 171.67, 86.52, 86.41, 78.06, 78.03,
51.61, 51.51, 50.95, 50.94, 39.22, 37.97, 35.12, 35.09, 28.23,
26.85, 26.05, 26.03, 23.83, 20.15, 20.09; Anal. Calc.: C, 54.74; H,
7.22; N, 13.68; B, 3.52. Found: C, 55.00; H, 7.28; N, 13.50; B,
3.26%.
A solution of stannous chloride (0.43 mmol) and concentrated
hydrochloric acid (0.07 mL) in methanol (1 mL) was stirred with
3a (0.29 mmol) in methanol (1 mL) followed for 0.5 h, then con-
centrated under reduced pressure. No evidence of reduction was
shown by 300 MHz 1H NMR and 75 MHz 13C NMR data.
5.7. Pinanediol (azidomethyl)boronate (6)
5.10. Pinanediol (2-aminoethyl-1-hydroxy)boronate hydrochloride
(10)
(S)-Pinanediol (bromomethyl)boronate (5) [19] was prepared
from diisopropyl (bromomethyl)boronate and (S)-pinanediol un-
der conditions similar to those used for preparation of 1. A solu-
tion of 5 (7.2 g, 26.4 mmol) in ethyl acetate (250 mL) was stirred
with a solution of sodium azide (17.1 g, 264 mmol) and tetrabu-
tylammonium bromide (4.25 g, 13.2 mmol) in water (70 mL) at
75 °C for 8 h. After cooling to room temperature the mixture
was extracted twice with ethyl acetate (2 ꢂ 50 mL) and washed
with water (3 ꢂ 50 mL). The combined organic layer was dried
over anhydrous magnesium sulfate and filtered. Removal of sol-
Pinanediol (1-acetoxy-2-azidoethyl)boronate (9) (1 g, 3.25
mmol) was dissolved in hydrogen chloride solution in dioxane
(4 M, 10 mL) and platinum dioxide (100 mg) was added. The mix-
ture was hydrogenated at 10 atm (145 psi), 20–25 °C, for 1 h. The
catalyst was removed by filtration and washed with ethanol and
the filtrate was evaporated. The residue was triturated with cold
pentane and dried under vacuum to give the hydroxyl derivative
10 as a gummy solid (825 mg, 92%). IR (neat): 3362, 2926, 1607,
vent on
methyl)boronate (6) (5.95 g, 96%); IR (neat): 2924, 2091, 1387,
1295 cmꢁ1 1H NMR d 4.36 (dd, J = 2.0, 8.9 Hz, 1H), 3.10 (s, 2H),
a rotary evaporator afforded (S)-pinanediol (azido-
1378 cmꢁ1 1H NMR: d 4.43 (d, J = 8.4 Hz, 1H), 3.66 (m, 2H), 3.10
;
(m, 2H), 2.34 (m, 2H), 2.05 (t, J = 5.3 Hz, 1H), 1.90 (m, 2H), 1.43
(s, 3H), 1.32 (s, 3H), 1.15 (d, J = 11.1 Hz, 1H), 0.88 (s, 3H);
13C NMR: 87.8, 79.4, 57.2, 52.2, 44.3, 44.2, 40.5, 38.9, 35.9, 29.0,
27.7, 27.1, 24.5.
;
2.30 (m, 2H), 2.07 (m, 1H), 1.92 (m, 2H), 1.43 (s, 3H), 1.3 (s,
3H), 1.11 (d, J = 11.1 Hz, 1H), 0.85 (s, 3H); 13C NMR d 86.65,
78.24, 50.84, 39.20, 37.90, 34.96, 28.27, 26.82, 26.28, 23.77. Anal.
Calc.: C, 56.20; H, 7.72; B, 4.60. Found: C, 56.70; H, 7.55; B,
4.72%.
5.11. Pinanediol (2-acetamido-1-acetoxyethyl)boronate (11)
A solution of pinanediol (2-aminoethyl-1-hydroxy)boronate
hydrochloride (10) (422 mg, 1.53 mmol) was dissolved in acetic
anhydride (4 mL) and stirred for 30 min. This mixture was then
cooled to ꢁ22 °C and triethylamine (0.47 mL, 3.4 mmol) was
added dropwise. The mixture was allowed to warm to 20–25 °C
for 2 h. Excess acetic anhydride was evaporated under vacuum
pump pressure. The crude mixture was extracted with diethyl
ether (3 ꢂ 50 mL) and washed with water (3 ꢂ 50 mL). The com-
bined organic layer was dried over anhydrous MgSO4 and filtered.
Removal of solvent on a rotary evaporator afforded 11 (243 mg,
49%). A sample was purified by recrystallization from diethyl
ether/pentane, then recrystallized twice from methylcyclohexane,
m.p. 146–149 °C (Fisher–Johns hot plate). IR (neat): 3286, 2919,
5.8. Pinanediol (1-chloro-2-azidoethyl)boronate (7)
(Dichloromethyl)lithium was prepared by the addition of
n-butyllithium (13.5 mmol) to dichloromethane (2 mL, 31.14
mmol) in anhydrous THF (100 mL) at ꢁ100 °C under argon. A
solution of azidoboronic ester 6 (92.44 g, 10.38 mmol) in anhy-
drous THF (15 mL) was added to the solution with vigorous stir-
ring. After 10 min, anhydrous zinc chloride (20.77 mmol) in
diethyl ether was added and the mixture was allowed to warm
to room temperature slowly with stirring it for 15 h. Diethyl
ether (200 mL) was added to the reaction mixture and washed
with saturated ammonium chloride (3 ꢂ 50 mL) to remove zinc
chloride, dried over anhydrous magnesium sulfate and concen-
trated on a rotary evaporator. The crude product was filtered
through a small silica gel column using 5% diethyl ether in pen-
tane to afford (S)-pinanediol-2-azido-1-chloroethylboronate
1728, 1634, 1576, 1451, 1373 cmꢁ1 1H NMR (CDCl3) d 5.97 (s,
;
1H), 4.26 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 4.11 (dd, J = 6.5 Hz, 4.1 Hz,
1H), 3.57 (m, 2H), 2.29 (m, 2H), 2.11 (s, 3H), 2.03 (t, J = 5.6 Hz,
1H), 1.98 (s, 3H), 1.85 (m, 2H), 1.39 (s, 3H), 1.28 (s, 3H), 1.24
(d, J = 11.1 Hz, 1H), 0.83 (s, 3H). 13C NMR (CDCl3) d 172.87,
170.05, 86.51, 78.08, 64.48 (broad, C connected to B), 51.20,
39.96, 39.42, 38.17, 35.28, 28.30, 27.00, 26.11, 23.99, 23.28,
(2.5 g, 85%); IR (neat): 2927, 2103, 1397, 1288 cmꢁ1 1H NMR d
;
4.40 (dd, J = 2.0, 9.0 Hz, 1H), 3.65 (m, 3H), 2.32 (m, 2H), 2.10
(m, 1H), 1.92 (m, 2H), 1.44 (s, 3H), 1.30 (s, 3H), 1.17 (d,
J = 11.4 Hz, 1H), 0.85 (s, 3H); 13C NMR d 87.1, 78.7, 54.4, 50.9,
39.1, 38.0, 34.9, 28.2, 26.8, 26.1, 23.8. No evidence for the diaste-
20.28; HRMS Calc. for
323.1890%.
C16H26BNO5: m/e 323.1904. Found:

2262
D.S. Matteson et al. / Journal of Organometallic Chemistry 693 (2008) 2258–2262
5.12. (4S,5S,10RS)-2-(10-Acetoxy-20-azidoethyl)-4,5-dicyclohexyl-
1,3,2-Dioxaborolane [(S,S)-DICHED (RS)-(1-acetoxy-2-
azidoethyl)boronate]
equipment was supported by NIH Grants RR0631401 and RR12948,
NSF Grants CHE-9115282 and DBI-9604689, and a Grant from the
Murdock Charitable Trust.
After it was found in a preliminary test that no more than a
few percent reaction occurred at 20–25 °C in 24 h [300 MHz 1H
NMR (CDCl3) d 2.13 (s), 4.33 (m)], a solution of (4S,5S,10R)-2-(20-
azido-10-chloroethyl)-4,5-dicyclohexyl-1,3,2-dioxaborolane (ent-
3) (2.5 g) and sodium acetate (1.5 g) in acetic acid (20 mL) was
stirred at 95 °C under argon for 20 h. After work up with diethyl
ether and water followed by additional washing of the ether
phase with water and sodium bicarbonate, concentration on a ro-
tary evaporator yielded 2.5 g of residue (7.35 mmol, ꢀ95%). Chro-
matography on silica and elution with 5% ether/pentane resulted
in removal of gross impurities but no change in isomer ratio as
judged by the multiplets centered at d 4.41; 300 MHz 1H NMR
(CDCl3) d 0.9–1.8 (m, ꢀ22 H, + s at d 1.6, ꢀ10 H), 2.134 and
2.139 (s + s, 3H), 3.49ꢁ3.64 (m, 2H), 3.89 + 3.91 (overlapping
d’s, J ꢀ 4.5 Hz, 2H), 4.31 (dd, J = 3.9 Hz, 7.5 Hz, 0.5H), 4.37 (dd,
J = 3.6 Hz, 7.8 Hz, 0.5H); 300 MHz 1H NMR (C6D6) d 0.6–1.6 (m,
ꢀ22 H, + s + s at d 1.36 and 1.37, ꢀ3 H), 2.92 (m, 1H), 3.02 (m,
1H), 3.52 (broad d, J ꢀ 4.5 Hz, 2H), 3.99 (m, 8 peaks of ꢀ equal
amplitude, 1H); 75 MHz 13C NMR + DEPT (C6D6) (dp = diastereo-
meric pair, separation in ppm) d 19.6 (CH3), 26.1 (dp 0.117,
CH2), 26.6 (dp 0.021, CH2) 27.7 (dp <0.02, CH2), 28.7 (dp 0.034,
CH2), 43.0 (dp 0.034, CH), 51.8 (dp 0.165, CH2), 65.1 (br, CB),
84.3 (CH), (C6D6 127.9 t), 171.6 (dp 0.062, C@O). HRMS (FAB) Calc.
for C18H31BN3O4 (M+H): 364.1211. Found: 364.2415.
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5.13. (+)- and (ꢁ)-Pinanediol (RS)-(2-acetamido-1-
acetoxyethyl)boronate (11, ent-11) from the DICHED ester
Portions (160 mg each) of (S,S)-DICHED 1-(RS)-(2-acetamido-1-
acetoxyethyl)boronate were treated separately with (+)-pinanediol
and (ꢁ)-pinanediol (75 mg each) in diethyl ether (5 mL) and meth-
anol (0.5 mL) overnight. Concentration followed by treatment with
pentane resulted in precipitation of the DICHED, and the pinanedi-
ol esters were further purified by chromatography on silica with
diethyl ether/pentane. There was no apparent difference between
the 1H NMR spectra of the (+)-pinanediol and (ꢁ)-pinanediol es-
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Acknowledgements
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Berlin, 1995.
We thank the National Science Foundation for support, Grant No
CHE-0353145. We thank Loralee Ohrtman for the conversion of 3a
to its acetoxy derivative prior to the similar preparation of 9, and
for an oral report of the conditions she used. The WSU NMR Center
[25] D.S. Matteson, M.L. Peterson, J. Org. Chem. 52 (1987) 5116–5121.
[26] W.C. Hiscox, D.S. Matteson, J. Org. Chem. 61 (1996) 8315–8316.