Waste-free and facile solid-state protection of diamines, anthranilic acid, diols, and polyols with phenylboronic acid

Article abstract of DOI:10.1002/chem.200304793

Phenylboronic acid (2) reacts quantitatively by ball-milling in the solid state with o-phenylendiamine, 1,8-diaminonaphthalene, anthranilic acid, pyrocatechol, pyrogallol, pinacol, bicyclic cis-diols, mannitol, and inositol to form the five- or six-membered cyclic phenyl-boronic amides or esters. Catalysts or other auxiliaries are strictly excluded as they are not required and would have to be removed after the reactions. These varied model reactions provide pure protected products without the necessity of further purifying workup and the potential for protection chemistry is demonstrated. Some of the reactions can also be quantitatively performed if stoichiometric mixtures of the reactants are co-ground or co-milled and heated to appropriate temperatures either below the eutectics or above the melting points. The temperatures are much higher in the latter case. Similar reactions in solution suffer from less than 100% yield of the mostly sensitive compounds that are difficult to purify and thus create much waste. The hydrolysis (de-protection) conditions of the products are rather mild in most cases. Therefore, this particularly easy access to heteroboroles, heteroborolanes, heteroborinones, heteroborines, and heteroborinines is highly valuable for their more frequent use in protective syntheses.

Full text of DOI:10.1002/chem.200304793

FULL PAPER
Waste-Free and Facile Solid-State Protection of Diamines, Anthranilic Acid,
Diols, and Polyols with Phenylboronic Acid
Gerd Kaupp,* M.Reza Naimi-Jamal, and Vladimir Stepanenko [a]
Abstract: Phenylboronic acid (2) reacts
quantitatively by ball-milling in the solid
state with o-phenylendiamine, 1,8-dia-
minonaphthalene, anthranilic acid, py-
rocatechol, pyrogallol, pinacol, bicyclic
cis-diols, mannitol, and inositol to form
the five- or six-membered cyclic phenyl-
boronic amides or esters. Catalysts or
other auxiliaries are strictly excluded as
they are not required and would have to
be removed after the reactions. These
varied model reactions provide pure
protected products without the necessity
of further purifying workup and the
potential for protection chemistry is
demonstrated. Some of the reactions
can also be quantitatively performed if
stoichiometric mixtures of the reactants
are co-ground or co-milled and heated
to appropriate temperatures either be-
low the eutectics or above the melting
points. The temperatures are much high-
er in the latter case. Similar reactions in
solution suffer from less than 100%
yield of the mostly sensitive compounds
that are difficult to purify and thus
create much waste. The hydrolysis (de-
protection) conditions of the products
are rather mild in most cases. Therefore,
this particularly easy access to hetero-
boroles, heteroborolanes, heterobori-
nones, heteroborines, and heterobori-
nines is highly valuable for their more
frequent use in protective syntheses.
Keywords: diamines ¥ environmen-
tally benign ¥ phenylboronic acid ¥
polyols ¥ solid-state reactions
been described. These cyclization reactions of 1,2-diamines
and 1,2-diols were performed in solution or at functionalized
polymer surfaces with yields ranging from 21 to 97%. We
have now found that they proceed quantitatively in the solid-
state or in stoichiometric melts, even though two equivalents
of water are released per ring closure and must be removed
during the reaction in some cases. For protection purposes, we
chose unsubstituted phenylboronic acid (2) because it is most
readily available and yields well crystallized protected prod-
ucts.
Introduction
Protection (deprotection) remains an important task in the
field of bi- or polyfunctional alcohols, acids, amines, and thiols
with mixed functionalities.[1] Both protection and deprotec-
tion should be easy and quantitative in order to save precious
components and to minimize waste. We describe here
particularly versatile applications of phenylboronic acid in
protection chemistry. The protection reactions occur quanti-
tatively in stoichiometric mixtures without solvents, catalysts,
or other auxiliaries. Deprotection is easily achieved by rather
mild techniques in most cases.
Aromatic 1,2- and peri-diamines: The most profitable solid-
state technique provides compound 3 in quantitative yield
without waste if equimolar mixtures of the reagents 1 (m.p.
103 1058C) and 2 (m.p. 217 2208C) are co-ground in a
mortar at room temperature and heated to 408Cin a vacuum
for 1 h. Alternatively the mixture of reagents can be melted at
100 1108Cin a vacuum, while the water of reaction is
removed by evaporation from the hot melt (Scheme 1). This
reaction is superior to the corresponding solution reaction,
which gave a 79%[3] or 92%[4] yield and required purifying
Results and Discussion
Free amino and hydroxy groups frequently require protection.
If they are present in 1,2- or in favorable 1,3-positions, cyclic
amides or esters may be formed for that purpose. The
synthesis of some 1,3,2-dioxaborolanes/-dioxaborinines,[2] and
1,3,2-diazaborolanes/-diazaborinines[3] (five- and six-mem-
bered heterocyclic aryl boronic acid esters and amides) has
[a] Prof. Dr. G. Kaupp, Dr. M. R. Naimi-Jamal, Dipl.-Chem.
V. Stepanenko
University of Oldenburg
Fakult‰t 5, Organische Chemie I
Postfach 2503, 26111 Oldenburg (Germany)
Fax : (‡49)441-7983-409
E-mail: kaupp@kaupp.chemie.uni-oldenburg.de
Scheme 1. Quantitative synthesis of 3 from a stoichiometric melt.
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DOI: 10.1002/chem.200304793
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4156 4160
workup. The deprotection of 3 has been described,[5] and it can
also be quantitatively performed in boiling aqueous Na2CO3.
1,8-Diaminonaphthalene (4) reacts with 2 in the solid state
at 08Cand provides the six-membered diazaborinine 5 in
quantitative yield (Scheme 2). Previously, 5 was obtained by
reaction of 4 with phenylboronic dichloride in benzene (3 h
reflux, 64%)[6] or with phenylboronic anhydride (100 1408C,
71%).[7]
Scheme 4. Quantitative solid-state synthesis of 9 in a ball-mill.
Scheme 2. Quantitative solid-state synthesis of 5 in a ball-mill.
Now, both products 3 and 5 can be obtained directly in the
pure state without the need for further purification when
starting with the pure reagents. There are no difficulties with
intermolecular bridging, and linear boronic amides do not
form with the new technique. Compound 5 is not easily
deprotected but requires strong acid or strong base.[6] It is
unusually stable, except for slow oxidation with oxygen, and
may be useful for electrophilic aromatic substitutions.
Scheme 5. Quantitative solid-state synthesis of 11 and its use as
protected reagent.
a
drying the product in a vacuum at 808C. The yields of 9 and 11
in solution were 51%[9] and 90%[2], respectively.
The free hydroxy group in 11 can be quantitatively
benzoylated to give 12 (Scheme 5). Conversely, the yield of
12 in the pyridine solution reaction was only 65%.[2]
Compound 12 is a precursor to 1-benzoyloxy-2,3-dihydroxy
benzene (13) by deprotection with mannitol.[2] The depro-
tection of 9 and 11 can also be achieved by heating with
aqueous NaHCO3 to 408Cfor 2 h.
Anthranilic acid: If equimolar mixtures of anthranilic acid (6)
and phenylboronic acid (2) are ball-milled, compound 7 with
its O,B,N six-membered ring is quantitatively formed, again
without waste (Scheme 3). Both, a primary amino and a
carboxylic acid group are protected here. The same product 7
was obtained in a solution reaction, however, in only 90%
yield.[3]
Aliphatic 1,2-diols: The cyclization reaction of aliphatic 1,2-
diols is equally versatile and waste-free with pinacol (14).
Ball-milling of a stoichiometric mixture of 14 and 2 at 08C
gives quantitatively 15 (Scheme 6). Previous reactions in
solution afforded 15 with yields of 59%[10] or 80%.[11]
Scheme 3. Quantitative solid-state synthesis of 7 in a ball-mill.
The deprotection of 7 with aqueous NaHCO3 at 908Cis
complete after 1 h to give the sodium salt of 6 and
PhB(OH)ONa.
Scheme 6. Quantitative solid-state synthesis of 15 in a ball-mill.
Reactions of natural a-amino acids with phenylboronic acid
have not been described in the literature. The a-amino acid l-
proline reacts with 2 in the solid state (608C) and in a melt
(1008C), however, it was not yet possible to get a pure cyclic
product due to facile hydrolytic deprotection. On the other
hand, the reaction shows promise as a route for obtaining
3,1,2-oxazaborilidin-4-ones if the water of reaction is effi-
ciently removed under the reaction conditions. N-acylated or
N-tosylated amino acids seem to lack reactivity and require
phenylboronic dichloride for their protection.[8]
Interestingly, also the [3.3.3]heteropropellanes 17 can be
quantitatively obtained by the solid solid technique when
stoichiometric mixtures of 16a or 16b[12] and 2 are ball-milled
at 50 or 958C, respectively (Scheme 7). The polyfunctional
Aromatic 1,2-diols: Pyrocatechol (8) and pyrogallol (10) react
quantitatively with phenylboronic acid when stoichiometric
mixtures are ball-milled at 808C(Scheme 4 and Scheme 5). In
the case of 11, the yield is increased from 98% to 100% by
Scheme 7. Quantitative solid-state synthesis of heteropropellanes 17.
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G. Kaupp et al.
FULL PAPER
propellanes 17 are remarkably stable crystalline compounds.
The deprotection of 15 and 17a, b in 0.01n HCl, followed
by neutralization is achieved under rather moderate con-
ditions.
Conclusion
Our solid-state or solvent-free techniques for obtaining cyclic
phenylboronic esters and amides are largely superior to their
syntheses in solvents, as we get the products in pure form
directly in quantitative yield when starting with stoichiometric
mixtures of pure reactants excluding auxiliaries. The neces-
sary reaction temperatures vary, but solid-state conditions can
be found at considerably lower temperatures than the melt
reactions in most cases. Finely co-ground or co-milled
powders can be heated to appropriate temperatures for
quantitative reaction in the solid state in favorable cases of
melting points. This option is of importance if the required
reaction temperature exceeds the more comfortable heating
capabilities of the milling equipment. Melt reactions suffer
from the higher temperatures that must be applied, but the
yield may also remain quantitative in favorable cases,
although the risk of side reactions increases in melt reactions.
Large amounts of water are released in the polyol reactions,
but it is not necessary to use the phenylboronic anhydride for
improvement as the water of reaction can be removed by
moderate heating in a vacuum. The high crystallinity of the
phenylboronic esters or amides is very favorable. Certainly,
extensions to tailor-made protections with substituted aryl-
boronic acids instead of 2 are possible, if required.
Remarkably, the same products occurred exclusively in the
solid-state polyol reactions, these products crystallized in
much lower yield from the solution reactions. Apparently, the
most stable conformations are reactive and lead to the more
stable boronic esters both in the solid state and in the liquid
state. However, it remains to be clarified if further products
remain in the mother liquors of the solution reactions. The
protection of diols, diamines, amino acids, and polyols is of
widespread importance in organic syntheses and the versa-
tility of the solid-state technique or, if necessary, the solvent-
free stoichiometric melt technique is particularly promising in
that respect. The deprotections of the various boronic esters
or amides are generally successful under mild conditions but
vary markedly. Thus, the cyclizations that are facilitated by
acid require weak base for the reversion, but acid-catalyzed
hydrolysis followed by neutralization is successful if the
cyclization requires elevated temperatures.
Polyhydroxy compounds: mannitol and inositol: Sugar alco-
hols and cyclic polyalcohols form both five- and six-mem-
bered ring heterocycles with phenylboronic acid.[13] Interest-
ingly, some of these reactions occur also in the solid state. This
observation is of great importance as such protection with
easy deprotection gains increased importance in carbohydrate
chemistry.
d-Mannitol (18) reacts quantitatively with three molecules
2 in the ball-mill to give the 1:2,3:4,5:6-product 19 (Scheme 8)
as a nonsticky powder which has the same structure as the
product obtained in solution in only 68% yield.[10, 13] The
Scheme 8. Quantitative solid-state reaction of mannitol with phenylbor-
onic acid.
(R,R, R, R)-configuration has been confirmed by X-ray crystal
structure analysis.[14] Interestingly, the solution-state chemis-
try of 18 and 2 seems to favor a cyclic diester of mannitol in
which both primary OH groups are free for chemical
reaction.[15] However, the crystals that separate from solution
are the triester 19. Avery easy partial deprotection in aqueous
solution is clearly indicated and can be used for selective
reactions of 19.
The cyclic hexol myo-inositol (20) reacts with phenyl-
boronic acid (2) in a 1:3 ratio in the ball-mill at 958Cto give
the racemic tris-borolic ester 21 with one five-membered and
two six-memebered rings according to the relative positions of
the OH groups in the initial chair conformation of 20 in 100%
yield (Scheme 9). Compound 21 corresponds in all respects to
Ten varied examples in this work cover a broad range and
should be helpful for further progress in this field of research
as the protections occur waste-free and provide the highly
sensitive products without the requirement for purifying
workup.
Scheme 9. Quantitative solid-state reaction of myo-inositol with phenyl-
boronic acid.
Experimental Section
Melting points were determined with
a Gallenkamp melting point
apparatus and are uncorrected. IR spectra were recorded with a Perkin-
Elmer 1720-X FT-IR spectrometer using potassium bromide pellets. All
NMR spectra were recorded on a Bruker WP 300 at 300 MHz (1H) or
75 MHz (13C). CDCl3/[D6]DMSO mixtures contained up to 20%
[D6]DMSO. All d values refer to the internal standard TMS. The 13C
resonances of the carbon atoms that were directly bound to the boron atom
were not always found due to the quadrupole nuclei 10B and 11B. No
particular effort was undertaken to make these signals visible as these did
the quantitatively obtained product from the melt at 2308C
and to the previously reported product from the correspond-
ing solution reaction (75%).[16] The molecular structure of 21
was confirmed by X-ray crystal structure analysis.[16] The
deprotection is quantitative if 21 is dissolved in 0.01n HCl and
left for 1 h at room temperature.
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Waste-Free Solid State Protection
4156 4160
not have a high diagnostic value. Mass spectra were obtained on a Finnigan
MAT 212 System. Uniform heating of the stoichiometric melts without
partial distillation or sublimation was carried out in closed flasks in a
preheated oven. The ball-mill for the 2 mmol runs was a Retsch MM 2000
swing-mill with a 10 mL stainless steel double-walled beaker with fittings
for circulating coolants. Two stainless steel balls with 12 mm diameter were
used. Ball-milling was performed at a 20 25 Hz frequency usually at room
temperature (without circulating liquid the temperature did not rise above
308C). Water of the appropriate temperature was circulated for heating or
cooling. Completion of the solid-state reactions was checked by IR
2-Phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15): Pinacol (14,
236 mg, 2.00 mmol) and 2 (244 mg, 2.00 mmol) were ball-milled at 08C
for 1 h. After drying in a good vacuum at room temperature, spectroscopi-
cally pure 15 (325 mg, 100%) was obtained; m.p. 35 378C; ref.[10]: 29
308C; ref. [11]: 28 30 8C. The hydrolysis of 15 was most easily achieved in
0.1n HCl at room temperature for 1 h and 14 was almost quantitatively
extracted with dichloromethane after neutralization.
6,8-Dimethyl-10,11-benzo- (17a) and 6,8-diphenyl-10,11-benzo-tricy-
clo[3.3.3.0]-3-bora-2,4-dioxa-6,8-diaza-9-oxo-7-thioxo-undecene-10 (17b):
Compound 16a[12] (265 mg, 1.00 mmol) or 16b[12] (388 mg, 1.00 mmol) and 2
(122 mg, 1.00 mmol) were ball-milled at 508Cor 95 8C, respectively, for 1 h.
After drying at 808Cin a vacuum 17a (350 mg, 100%) or 17b (475 mg,
100%) was obtained in pure form.
1
spectroscopy in KBr and weight, and product purity by m.p. and H NMR
spectroscopy.
2-Phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (3)
Alternatively, co-ground 1:1 mixtures of 16a, b and 2 were heated to 1408C
for 1 h to form 17a, b in 100% yield.
a) Solid-state reaction: A mixture of o-phenylendiamine (1, 108 mg,
1.00 mmol) and phenylboronic acid (2, 122 mg, 1.00 mmol) was co-ground
at room temperature and then heated to 408Cin a vacuum for 1 h to give
pure 3 (195 mg; 100%) after drying at 808Cin a vacuum.
17a: m.p. 222 2248C(decomp); IR (KBr): nÄ ˆ 1733, 1603, 1333, 1076,
1033, 750, 698, 661, 619, 510 cmÀ1
;
1H NMR (CDCl3): d ˆ 8.00 7.78 (m,
5H), 7.79 (m, 1H), 7.50 (m, 1H), 7.38 (m, 2H), 3.52 (s, 3H), 3.49 ppm (s,
3H); 13C NMR (CDCl3): d ˆ 198.0, 189.9, 144.6, 137.3, 135.3 (2C), 134.8,
132.8, 131.8, 128.0 (2C), 126.2, 124.9, 100.6, 97.8, 30.1, 29.8 ppm; HRMS
(70 eV): calcd for C18H15BN2O3S: 350.0896; found 350.0896.
b) Melt reaction: A mixture of o-phenylendiamine (1, 216 mg, 2.00 mmol)
and phenylboronic acid (2, 244 mg, 2.00 mmol) was heated in an evacuated
100 mL flask in a drying oven for 30 min, briefly evacuated, heated for
another 30 min, and evacuated at 808Cfor 1 h. A quantitative yield
(388 mg, 100%) of 3 (m.p. 207 À 2088C; ref. [4]: 213 214 8C) was obtained.
17b: m.p. 257 2598C; IR (KBr): nÄ ˆ 3427, 1736, 1604, 1440, 1378, 1329,
1101, 747, 692 cmÀ1
;
1H NMR (CDCl3): d ˆ 8.00 7.80 (m, 3H), 7.60
The deprotection of 3 was achieved according to reference [5] or by
refluxing 3 (200 mg) in 5% aqueous Na2CO3 solution (10 mL) for 8 h,
7.30 ppm (m, 16H); 13C NMR (CDCl3): d ˆ 189.1, 182.8, 144.6, 137.0,
136.0, 135.8, 135.5 (2C), 134.6, 133.0, 131.9, 129.8 (2C), 129.5 (2C), 129.3
(2C), 129.2 (3C), 129.1, 128.2 (2C), 126.0, 125.4, 101.7, 98.8 ppm; HRMS
(70 eV): calcd for C28H19BN2O3S: 474.1209; found 474.1209.
followed by extraction with dichloromethane to obtain
quantitative yield.
1 in almost
2-Phenyl-2,3-dihydro-1H-2-boraperimidine or 2-phenyl-2,3-dihydro-1H-
naphtho[1,8-de][1,3,2]diazaborinine (5): Crystalline 1,8-diaminonaphtha-
lene (4, 158 mg, 1.00 mmol) and 2 (122 mg, 1.00 mmol) were ball-milled at
08Cfor 1 h. Compound 5 was dried in a vacuum at 508Cand obtained in
spectroscopically pure form (244 mg, 100%). It was stored under argon or
N2. 5: m.p. 90.5 91.58C; ref. [6]: 92.5 93.5 8C(corrected, under N 2; after
three recrystallizations and four sublimations). IR (KBr): nÄ ˆ 2433, 1628,
Deprotection (removal of the borole ring) of 17a, b to obtain 16a, b with
quantitative yield was achieved by hydrolysis in 0.01n HCl, neutralization,
filtration, and washing with water.
(2R,3R,4R,5R)-1:2,3:4,5:6-O1:O2,O3:O4,O5:O6-tris(phenylboranato)-d-
mannitol (19): d-Mannitol (18, 364 mg, 2.00 mmol) and 2 (732 mg, 6 mmol)
were ball-milled at room temperature for 1 h and the solid nonsticky
product (IR) dried at 808Cin a vacuum. Compound 19 (880 mg, 100%) was
obtained in pure form; m.p. 132 1338C, ref. [10]: 134 1358C. It was
identical to the product obtained from solution in 66% yield[10] and
structurally confirmed by X-ray diffraction.[14]
rac-1:2,3:5,4:6-O1:O2,O3:O5,O4:O6-tris(phenylboronato)-myo-inositol (21):
A mixture of myo-inositol (20) (360 mg, 2.00 mmol) and 2 (732 mg,
6 mmol) was ball-milled at 958Cfor 1 h or melted in a high vacuum at
2308Cfor 1 h in a 250 mL flask. Pure nonsticky 21 (875 mg, 100%) was
obtained in both cases; m.p. 228 2308C; ref. [16]: 204 208 8C . The1H and
13CNMR spectra were identical with those of the product from the
analogous solution reaction,[16] the structure of which was confirmed by
X-ray diffraction.[16]
1603, 1515, 1485, 1414 cmÀ1
;
1H NMR (CDCl3): d ˆ 7.70 7.60 (m, 2H),
7.50 7.35 (m, 3H), 7.15 7.08 (m, 2H), 7.05 7.00 (m, 2H), 6.42 (yd, 2H),
6.15 ppm (br p, 2NH); 1H NMR (CDCl3/[D6]DMSO, 1:1 v/v): d ˆ 7.92 7.73
(m, 2H), 7.50 7.19 (m, 3H ‡ 2NH), 7.13 7.00 (m, 2H), 6.98 6.85 (m, 2H),
6.50 ppm (yd, 2H); 13C NMR (CDCl3): d ˆ 141.1 (2C), 136.3, 134.0, 131.4
(2C), 130.1, 128.1 (2C), 127.5 (2C), 119.8, 117.6 (2C), 105.9 ppm (2C);
13C NMR (CDCl3/[D6]DMSO, 1:1 v/v): d ˆ 141.2 (2C), 135.7, 133.6, 131.4
(2C), 129.5, 127.4 (2C), 127.0 (2C), 119.0, 116.5 (2C), 105.4 ppm (2C);
HRMS (70 eV): calcd for C16H13BN2: 244.1172; found 244.1170.
2-Phenyl-1,2-dihydro-benzo[a][1,3,2]-oxazaborinin-4-one: Crystals of an-
thranilic acid (6, 274 mg, 2.00 mmol) and 2 (244 mg, 2.00 mmol) were ball-
milled for 1 h at room temperature. After drying at 808Cin a vacuum,
spectroscopically pure crystals of 7 (445 mg, 100%) were obtained; m.p.
224 À 2268C; ref. [3]: 228 8C. Complete deprotection was achieved by
boiling 7 (200 mg) in 5% NaHCO3 solution (20 mL) for 1 h.
The deprotection of 21 to recover 20 was achieved in 0.01n HCl solution at
room temperature for 1 h.
2-Phenyl-1,3,2-benzodioxaborole (9): Pyrocatechol (8, 110 mg, 1.00 mmol)
and 2 (122 mg, 1.00 mmol) were ball-milled at 808Cfor 1 h or co-ground in
Acknowledgement
a mortar and heated to 1158Cfor 1 h. Compound
9 was obtained in
This work was supported by the Deutsche Forschungsgemeinschaft. We
thank Mrs. Ludmila Hermann for her reliable help in the experimental
work.
spectroscopically pure form (196 mg, 100% in both cases) after drying at
808Cin a vacuum; m.p. 108 8C; ref. [9]: 110 8C. The deprotection of 9
(200 mg) in 5% NaHCO3 (10 mL) was complete after 2 h at 408C.
Compound 8 was extracted with dichloromethane.
2-Phenyl-1,3,2-benzodioxaborole-4-ol (11): Pyrogallol (10, 252 mg,
2.00 mmol) and 2 (244 mg, 2.00 mmol) were co-ground in a mortar and
heated in an evacuated flask to 408Cfor 2 h in a drying oven. After drying
at 808Cin a vacuum, spectroscopically pure 11 (425 mg, 100%) was
obtained; m.p. 163 1658C; ref. [2]: 166 8C.
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FULL PAPER
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Received: January 31, 2003
Revised: April 7, 2003 [F4793]
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