Tetrahedron 63 (2007) 8645–8657

New boron(III)-catalyzed amide and ester condensation

reactions
Toshikatsu Maki,a Kazuaki Ishiharaa,* and Hisashi Yamamotob,*
a
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
b
Department of Chemistry, The University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA
Received 9 February 2007; revised 26 March 2007; accepted 27 March 2007
Available online 31 March 2007

Abstract—In 1996, we reported that benzeneboronic acids bearing electron-withdrawing groups at the meta- or para-position are highly ef-
fective catalysts for the amide condensation reaction in less-polar solvents. In this paper, we report that N-alkyl-4-boronopyridinium halides
are more effective catalysts than the previous ones in more polar solvents. N-Alkyl-4-boronopyridinium halides are effective not only for
amide condensation between equimolar mixtures of carboxylic acids and amines but also for the esterification of a-hydroxycarboxylic acids
in alcohol solvents. Furthermore, perchlorocatecholborane is more effective than areneboronic acids for the amide condensation of sterically
demanding carboxylic acids. In addition, Lewis acid-assisted Brønsted acid (LBA), which is prepared from a 1:2 M mixture of boric acid and
tetrachlorocatechol, is effective for the Ritter reaction from alcohols and nitriles to amides.
Ó 2007 Elsevier Ltd. All rights reserved.

1. Introduction X

cat. Y B(OH)2
It is becoming increasingly desirable to replace current
chemical processes with more environmentally benign alter- R2 X 1 (X=CF3, Y=H)
natives.1 The condensation of carboxylic acids with alcohols R1CO2H + H N
ArH, azeotropic reflux
or amines is one of the most fundamental and important re- R3

actions in organic synthesis.2 To promote atom efficiency and

to avoid the generation of environmental waste, the use of H X
O O O
stoichiometric amounts of condensing reagents should be B Y R2
R1 O R1 N
avoided. Therefore, the direct condensation of equimolar R3
mixtures of carboxylic acids with alcohols or amines using N X
H N H 2 R3
3 R
small amounts of catalysts is the most ideal method. R 2 R

In 1996, we found that the dehydrative condensation of equi- Scheme 1. Boronic acid-catalyzed dehydrative amide condensation
reaction.
molar mixtures of carboxylic acids and amines or ureas pro-
ceeds under azeotropic reflux conditions with the removal
of water in less-polar solvents such as toluene or xylene demanding substrates. In this paper, we report that various
in the presence of benzeneboronic acids bearing electron- boron(III) compounds such as boronic acids (2 and 3a–d),
withdrawing groups at the meta- or para-position, such as boric acid, and catecholborane derivatives (4a–c) are highly
3,4,5-trifluorobenzeneboronic acid, 3,5-bis(trifluoromethyl)- effective catalysts for the amidation,4,6 esterification,5 and/
benzeneboronic acid (1), and 3,5-bis(perfluorodecyl)benz- or the Ritter reaction6 (Fig. 1).
eneboronic acid (Scheme 1).3

However, the scope of suitable substrates has been limited 2. Results and discussion
because the catalytic activities of these neutral boronic acids
are greatly reduced in polar solvents and for sterically 2.1. Amide condensation reaction catalyzed by
N-alkyl-4-boronopyridinium salts
Keywords: Boron(III); Dehydrative condensation reaction; Amidation;
Esterification; Ritter reaction; Green chemistry.
* Corresponding authors. Tel.: +81 52 789 3331; fax: +81 52 789 3222 In 2000, we found that 4-borono-N-methylpyridinium iodide
(K.I.); tel.: +1 773 702 5059; fax: +1 773 702 0805 (H.Y.); e-mail (2) was effective as a polar-solvent-tolerable catalyst for
addresses: [email protected]; [email protected] amide condensation.7 Cationic boronic acid 2 was much

0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.157
8646 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657

Table 1. Catalytic activities of boronic acids

CO2H O NHBn
polystyrene resin catalyst (5 mol %)
+ H2NBn
toluene (5 mL)
(2 mmol)
[emim][OTf] (1 mL)
N+ B(OH) 2 R N+ B(OH)2 (2 mmol) azeotropic reflux, 2 h
I– X–
2 3a (R = CH2, X = Cl) Entry Catalyst Conv. (%) Entry Catalyst Conv. (%)
3b (R = (CH2)2, X = Br)
3c (R = (CH2)2, X = NTf2) 1 2 59 3 7 43
3d (R = (CH2)4, X = Br) 2 5 54 4a 8 8
B(OH) 3 a
Compound 7 did not dissolve under these conditions.
Cl Cl Cl
Cl O Cl O O Cl 2). 3- and 4-Pyridineboronic acids, 7 and 8, were less active
B R B
O O O
than the corresponding boronopyridinium iodides (entries 3
Cl Cl Cl
H and 4). The catalytic activity of 8 was quite low, probably be-
Cl Cl Cl
4a (R=OH) 4c
cause of its low solubility under these reaction conditions.
4b (R=H)
In the course of the experiment in which 2 was heated in
Figure 1. Boron(III) compounds as catalysts for dehydrative condensation
reaction.
DMF at 120  C, we observed that 2 completely changed to
a yellow precipitate within 1 h, and then gradually under-
went hydrolytic protodeboration. We isolated this yellow
more active than neutral boronic acids in polar solvents, such precipitate as an orange crystal from water. Surprisingly,
as anisole, acetonitrile, and N-methylpyrrolidinone (NMP) the crystal was unambiguously confirmed to be a dodecamer
because the boron atom in 2 shows greater Lewis acidity of 2, [2]12, by single-crystal X-ray diffraction (Fig. 2). To the
in polar solvents.7 Thus, 2 was successfully used as a catalyst best of our knowledge, this is the first example of a dodeca-
for the direct polycondensation of arenedicarboxylic acids mer of an arylboronic acid. Interestingly, [2]12 was dissolved
with diaminoarenes in a mixed solvent of terphenyl and N- and stable even in water because the 12 hydrophilic pyridi-
butylpyrrolidinone (NBP). In 2001, Wang et al. reported 3- nium ion moieties were oriented on the outside of [2]12.
borono-N-methylpyridinium iodide (5) and N-polystyrene
resin-bound 3-boronopyridinium chloride (6) as amide con- Next, the catalytic activities of 2 and [2]12 (5 mol % for
densation catalysts.8 In this section, we report that N-alkyl- B-atom) were compared in the amide condensation of 4-
4-boronopyridinium salts are more thermally stable than phenylbutyric acid with benzylamine under azeotropic reflux
N-alkyl-3-boronopyridinium salts.4 A homogeneous catalyst conditions in toluene with the removal of water (entries 1
2 could be reused through the use of an ionic liquid–toluene and 2, Table 2). The catalytic activity of [2]12 was much
biphasic system. Furthermore, we developed N-polystyrene lower than that of 2. Fortunately, the catalytic activities of
resin-bound 4-boronopyridinium salts 3a–d as heteroge- 2 and [2]12 were dramatically improved in biphasic solvents
neous amide condensation catalysts, which could be reused of toluene and [emim][OTf] (entries 3 and 4). These results
even in a single solvent such as toluene. can be understood in terms of the good stability of 2 and the
good solubility of 2 and [2]12 in the presence of [emim]-
According to some reports,9 the thermostability of pyridine- [OTf]. In contrast, 2 was partially soluble in toluene but [2]12
boronic acids for hydrolytic protodeboration increases in the was insoluble. It is likely that 2 is regenerated from [2]12 by
order: 2-pyridineboronic acid<<3-pyridineboronic acid hydrolysis in the presence of [emim][OTf]. Furthermore,
(7)<4-pyridineboronic acid (8). First, the thermostability [emim][OTf] should play an important role in suppressing
of N-methyl boronopyridinium iodides was investigated the condensation of 2 to [2]12. Thus, the amide condensation
under heating at 120  C in DMF. The half-life of 2 was 8 h
under the above conditions. On the other hand, 5 was com-
pletely decomposed to boric acid and N-methylpyridinium
iodide within 8 h via hydrolytic protodeboration. In contrast,
7 and 8 were stable even after heating at 120  C for 1 day. 2-
Borono-N-methyl boronopyridinium iodide could not be
prepared from 2-pyridineboronic acid because of its high
sensitivity to hydrolysis. Thus, we determined their thermo-
stabilities, which increased in the order 2-pyridineboronic
acid<<5<2<78. Next, the catalytic activities of pyridine-
boronic acids and boronopyridinium iodides were examined
for the model amide condensation reaction of cyclohexane-
carboxylic acid with benzylamine in 5:1 (v/v) biphasic
solvents of toluene and 1-ethyl-3-methylimidazolium tri-
fluoromethanesulfonate [emim][OTf]. The reactions were
carried out under azeotropic reflux conditions with the re-
moval of water for 2 h. The results are shown in Table 1.
As expected, 2 was the most active catalyst (entry 1). The Figure 2. X-ray crystal structure of dodecamer [2]12, [CH3NC5H4-
catalytic activity of 5 was slightly lower than that of 2 (entry BO14/12]12I8$10H2O. Water is omitted for clarity.
 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657 8647

Table 2. Catalytic activities of 2 and [2]12 for amide condensation Table 3. Direct amide condensation reaction catalyzed by 2
Ph Ph 2 (5 mol %) O
catalyst R1CO2H + R2R3NH R3
+ BnNH2 toluene (5 mL) R1 N
toluene (5 mL) (2 mmol) (2 mmol)
(2 mmol) O [emim][OTf] (1 mL) R2
CO2H [emim][OTf] (1mL) azeotropic reflux
(2 mmol) azeotropic reflux NHBn
Entry Time (h) Product Yield (%)
Entry Catalyst (mol %) Time (h) Yield (%) O

1a 2 (5) 1 41 1 6 NHBn 92
2a [2]12 (10)b 1 15
3 2 (5) 1 74
O
4 [2]12 (5)c 1 75
5 2 (5) 5 >99 2 18 Ph Bn 95
N
6d 2 (5) 5 >99
7e 2 (5) 5 >99
OMe
8 1 (5) 1 88 5 (First) 98 (First)
3a NHBn
9f 1 (5) 1 7 5 (Second) Ph 93 (Second)
5 (Third) O
95 (Third)
a
Only toluene was used as a solvent.
b
Compound [2]12 (10 mol % for B-atom) was used. OH
c
Compound [2]12 (5 mol % for B-atom) was used. 4b 18 NHBn 91
d
Compound 2 used in entry 5 was recovered and reused in entry 6. Ph
e O
Compound 2 used in entry 6 was recovered and reused in entry 7.
f
A solution of 1 in [emim][OTf] used in entry 8 was recovered and reused OMe
in entry 9. NHPh
5b 18 Ph 80
O
went to completion in the presence of 5 mol % of 2 in tolu- O
ene/[emim][OTf] (5:1 (v/v)) within 5 h (entry 5). After 6b 10 NBn 91
amide condensation, the desired amide was obtained in H
quantitative yield by repeated extraction with Et2O from an
O
[emim][OTf] layer. Compound 2 remained in the [emim]-
7b 3 90
[OTf] layer. Thus, a solution of 2 in [emim][OTf] was Ph NBn
repeatedly reused for the same amide condensation reac- H
tion without any loss of catalytic activity (entries 6 and 7). O
Neutral boronic acid 1 was also effective in the presence of 8b 6 98
Ph NHBn
[emim][OTf] because Lewis acidity of [emim][OTf] was O
much weaker than those of polar organic solvents such as a,b 5 (First) 99 (First)
THF and DMF (entry 8). However, 1 remained in a toluene 9 5 (Second) NBn 98 (Second)
5 (Third) H 99 (Third)
layer without being extracted with [emim][OTf] (entry 9). NC
a
A solution of 2 in [emim][OTf] was reused three times.
To explore the generality and scope of the amide condensa- b
o-Xylene was used as a solvent in place of toluene.
tion catalyzed by 2 in the presence of [emim][OTf], various
substrates were examined. Representative results are shown
in Table 3. Not only aliphatic but also aromatic substrates experimental results suggest that 6 was gradually decom-
were condensed in the presence of 5 mol % of 2.10 The amide posed to N-polystyrene-bound pyridinium chloride and boric
condensation of less-reactive substrates proceeded well un- acid by hydrolytic protodeboration. In contrast, no loss of
der azeotropic reflux conditions in o-xylene in place of tolu- catalytic activity was observed for our new N-polystyrene-
ene. Functionalized substrates such as conjugated carboxylic bound boronic acid 3a even after it was reused more than
acids, a-hydroxycarboxylic acids, a-alkoxycarboxylic acids, 5 times. The high catalytic activity of 3a, which was ob-
and cyanobenzoic acids were also applicable. Furthermore, served even in the absence of [emim][OTf], can be under-
a solution of 2 in [emim][OTf] was repeatedly reused without stood by assuming that a polymer-support may prevent
any loss of activity. dodecamerization of the 4-boronopyridinium chloride moi-
ety in 3a.
Next, to recover and reuse N-alkyl-4-boronopyridinium
halides without any ionic liquids, we prepared N-polystyrene- Table 4. Recovery and reuse of 6 and 3aa
bound 4-boronopyridinium chloride (3a) as well as N-poly- Run Conv. (%)
styrene-bound 3-boronopyridinium chloride 6, which had
Catalyst 6 Catalyst 3a
been developed by Wang and co-workers.8 Catalysts 6 and
3a (5 mol %) were recovered by filtration and reused five 1h 3h 5h 1h 3h 5h
times for the amide condensation reaction of 4-phenylbuty- 1 64 93 98 68 94 98
ric acid with benzylamine under azeotropic reflux conditions 2 53 90 98 67 94 98
with the removal of water (Table 4). Unfortunately, the rate 3 50 85 94 69 93 98
of the reaction catalyzed by 6 decreased every time 6 was 4 40 76 88 69 93 98
5 28 60 74 70 92 96
reused. The existence of boric acid was confirmed by 11B
a
NMR analysis of the filtrate after amide condensation. These See the equation in Table 2.
8648 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657

Table 5. Amide condensation reaction catalyzed by 3a H

O O OR2
O R2OH
3a (5 mol %) B B
R1CO2H + R2R3NH R3 Ar O R1 –R1CO2H, –H2O Ar OR2
toluene (5 mL) R1 N
(2 mmol) (2 mmol)
azeotropic reflux R2
R2R3NH + R2OH
Entry Time (h) Product Yield (%) –R1CO2H, –H2O

O O
R2R3NH
1 10 93 R3
NHBn –H2O R1 N
R2
O
1 (5 mol%)
2 20 Ph Bn 92 Ph BnNH2 (1 equiv) Ph
N
additive BnOH
OMe toluene
5 (First) 95 (First)
a NHBn CO2H azeotropic reflux CONHBn
3 5 (Second) Ph 95 (Second) 1h
5 (Third) O
94 (Third)
O without BnOH 96% yield
a,b 5 (First) 94 (First) 9% yield
4 NBn with BnOH (1 equiv)
5 (Second) 92 (Second) (benzyl ester,
5 (Third) H 94 (Third) <1% yield)
NC
a Scheme 2. Amide condensation versus ester condensation.
Compound 3a was reused three times.
b
o-Xylene was used as a solvent in place of toluene.
chemoselective esterification of a-hydroxycarboxylic acids
with excess alcohol as solvents even at ambient temperature
Next, the effects of several linkers between N-polystyrene (Scheme 3).11 This unexpected reactivity of a-hydroxycarb-
resin and 4-boronopyridinium ion were examined. The cat- oxylic acids with alcohols can be understood by considering
alytic activity and thermal stability of N-polystyrene-bound that thermally stable 2,2-dialkoxy-4-oxo-1,3,2-dioxaboro-
catalyst 3b linked with ethylene and N-polystyrene-bound lan-2-uide (9) is preferentially produced as an anionic active
catalyst 3d linked with butylene were the same as those of intermediate even in the presence of excess alcohol. Based on
3a linked with methylene. The effect of a counter anion was Houston’s report,11 we explored the efficacy of boric acid, 1,
also examined. Unexpectedly, no difference in catalytic and 2 as catalysts for the esterification of a-hydroxycarboxy-
activity was seen between counter anions such as Cl (3a), lic acids. In this section, we report that 2 is a more effective
Br (3b and 3d), and NTf 2 (3c). After the amide condensa- catalyst than boric acid for the esterification of a-hydroxy-
tion reaction, 3a was repeatedly washed with 1 M HCl aque- carboxylic acids in excess alcohol solvents (Houston’s con-
ous solution and ethyl acetate to be reused in the next ditions). On the other hand, boric acid is a more effective
reaction. When the treatment of 3a with 1 M HCl aqueous esterification catalyst for equimolar mixtures of a-hydroxy-
solution was abbreviated, the catalytic activity was some- carboxylic acids and alcohols.
what reduced. This unexpected decrease in the catalytic
activity of 3a can be understood by considering that chloride B(OH)3
anions of 3a would be partially exchanged to carboxylate OH R1 O OR2
(10–20 mol %)
B– H+
anions through the amide condensation. Therefore, the acidic R1 CO2H R2OH O OR
2
O
treatment of 3a was significant to reactivate 3a. Although we (excess)
9
didn’t ascertain whether other N-polystyrene-bound cata- OH
lysts 3b–d require the same acidic treatment for reactivation,
the acidic treatment would assure reactivation of 3b–d. R1 CO2R2

Scheme 3. Houston’s boric acid-catalyzed esterification.

To ascertain the generality and scope of the amide conden-
sation catalyzed by 3a, several substrates were examined First, the catalytic activities of boric acid, neutral boronic
in the absence of ionic liquid (Table 5). Compound 3a acid 1, and cationic boronic acid 2 were compared in the
was sufficiently active, like 2, regardless of the substrates esterification of mandelic acid in several excess alcohols
examined. (Table 6). As expected, boric acid was not very effective.
Compound 1 was also less active in polar solvents like alco-
2.2. Ester condensation reaction of a-hydroxycarboxylic hols. In each case, 2 gave the best results, probably because 2
acids catalyzed by boron(III) compounds was a tolerable cationic Lewis acid catalyst in polar alcohols.
Although 2 is known to be condensed to a less-active do-
Generally, boron(III) compounds were much less effective decamer under dehydrative conditions,5 this is prevented by
for the esterification of simple carboxylic acids because an excess alcohol.
alkoxyborane species was preferentially produced rather
than the desired acyloxyborane species (Scheme 2).3a To explore the generality and scope of the esterification
catalyzed by 2 in excess alcohol, various substrates were
In 2004, however, Houston et al. reported that boric acid examined in the presence of 5 mol % of 2.12 Representative
[B(OH)3, 10–20 mol %] was effective as a catalyst for the results are shown in Table 7. Not only a-hydroxycarboxylic
 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657 8649

Table 6. Catalytic activities of boric and boronic acids Table 7. Esterification of hydroxycarboxylic acids in alcohols catalyzed
OH OH by 2
B(III) (5 or 10 mol %)
2 (5 mol %)
Ph CO2H R2OH (5 mL) Ph CO2R2 RCO 2H RCO 2R2
(2 mmol) (2 mmol) R2OH (5 mL)

Entry R2OH Temp, time (h) Conv. (%) Entry Temp, time (h) Product Yield (%)
B(OH)3 1 2 OH
a
1 rt, 10 93
1 MeOH rt, 2 28 48 77 Bn CO 2Me
2a EtOH rt, 5 24 19 43
OH
3b i-BuOH Reflux, 1 36 32 83
2 Reflux, 6 99
4a i-PrOH Reflux, 5 29 14 52 Ph CO 2i-Bu
5b (CH2OH)2 80  C, 1.5 48c 29c 83c
OH
a
Catalyst (10 mol %) was used. 3 rt, 10 96
b Bn CO2Me
Catalyst (5 mol %) was used.
c
2-Hydroxyethyl mandelate was produced.
OH
4 Reflux, 15 92
CO2Me
acids but also b-hydroxycarboxylic acids were condensed. OH
In the esterification of 4-hydroxyisophthalic acid, the 3-hy- 5 Reflux, 4 95
Ph CO 2Et
droxycarbonyl group was selectively reacted (entry 12).
The esterification condensation of less-reactive secondary OH
alcohols and aromatic carboxylic acids proceeded well 6a Reflux, 21 81
Ph CO 2i-Pr
with the use of 10 mol % of 2 (entries 6, 11, and 12). b-Hy-
droxycarboxylic acids bearing a benzyloxycarbonylamino OH
80  C, 5 O
group at the a-position also reacted (entries 13 and 14). 7 Ph OH 97
Although ethylene glycol is known to react with boronic O
acid, leading to the corresponding cyclic boronic ester, ester- OH
ification with mandelic acid was unexpectedly preferred 8a Reflux, 15 MeO2C 95
CO2Me
(entry 7).
OH
Next, to recover and reuse homogeneous catalyst 2, 9a Reflux, 23 EtO2C 86
CO2Et
N-polystyrene-bound 4-boronopyridinium chloride (3a) was
examined as a heterogeneous catalyst. Compound 3a was OH
recovered by filtration and reused 10 times without any loss EtO2C
10a Reflux, 18 CO2Et 92
of activity for the esterification of mandelic acid in excess
isobutanol under reflux conditions (Table 8).13 OH

OH
Next, the correlation between the catalytic activity of 11 Reflux, 17 85
boron(III) compounds and the molar ratio of mandelic CO2i-Bu
acid and butanol was examined for esterifications catalyzed OH
by 2 mol % of boric acid, 1, and 2. The conversion to butyl 12b,c Reflux, 20 84
mandelate after heating under reflux conditions in toluene HO2C CO2i-Bu
for 1 h was plotted in terms of the molar ratio of mandelic
NHCO2Bn
acid to butanol (Fig. 3). Surprisingly, boric acid was the 13 Reflux, 20 93
HO
most active catalyst with a molar ratio of mandelic acid/ CO2Me
butanol of >1:2. On the other hand, 2 was the most active cat- NHCO2Bn
alyst with a molar ratio of mandelic acid/butanol of <1:3. In
14 Reflux, 22 CO2Me 89
contrast, 1 was less active than boric acid and 2 regardless of
OH
the molar ratio of mandelic acid/butanol. Two phenomena
that were common to these three catalysts were noted: (1) a
Dicarboxylic acid was used as a substrate.
b
excess mandelic acid accelerated the esterification, and (2) c
Compound 2 (10 mol %) was used.
excess butanol suppressed the esterification, probably be- Diisobutyl 4-hydroxyisophthalate and 2-hydroxy-5-(isobutoxycarbonyl)-
benzoic acid were produced in respective yields of 5 and 2%.
cause excess butanol diluted the concentration of mandelic
acid and the Lewis basicity of excess butanol weakened
the Lewis acidity of catalysts. However, 2 was still active examined in the presence of 5 mol % of boric acid in toluene
in the presence of excess butanol because of its ability to tol- under azeotropic reflux conditions (Table 9).12 Not only
erate polar compounds. Therefore, the addition of 4w5 equiv a-hydroxycarboxylic acids and primary alcohols but also
of butanol was more suitable for the esterification catalyzed b-hydroxycarboxylic acids and secondary alcohols were
by 2. applicable. The esterification of less-reactive substrates such
as conjugated carboxylic acids and secondary alcohols re-
To ascertain the generality and scope of the esterification quired 10 mol % of boric acid in toluene or xylene. Mercap-
of equimolar mixtures of a-hydroxycarboxylic acids and tocarboxylic acid was less reactive than the corresponding
alcohols catalyzed by boric acid, several substrates were hydroxycarboxylic acids (entries 1–3 vs entry 7).
8650 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657

Table 8. Recovery and reuse of 3a for esterification Table 9. Esterification of equimolar mixtures of hydroxycarboxylic acids
OH OH and alcohols catalyzed by boric acid
3a (10 mol %)
B(OH)3 (5 mol %)
Ph CO2H i-BuOH (2.5 mL) Ph CO2i-Bu RCO 2H + R2OH RCO 2R2
(1 mmol) toluene (5 mL)
(2 mmol) (2 mmol)
azeotropic reflux

Run Conv. (%) Run Conv. (%)

Entry Time (h) Product Yield (%)
1 96 6 99
2 99 7 98 OH
3 98 8 95 1 4 93
Ph CO2C8H17
4 99 9 97
5 96 10 95 OH
2 21 99
CO2C8H17

The boric acid-catalyzed chemoselective esterification of a- OH

3 21 90
hydroxy-a-methylpropanoic acid proceeded in the presence Ph CO2C8H17
of 4-phenylbutyric acid or benzoic acid (Scheme 4). Houston HO CO2C8H17
previously reported a similar boric acid-catalyzed chemo- 4a 21 87
selective esterification in excess alcoholic solvents.11 How- HO CO2C8H17
ever, our new procedure using boric acid does not require
the use of excess substrates. OH
O
5a 20 82
Why was the catalytic activity of boric acid remarkably in- O
creased in the presence of excess a-hydroxycarboxylic acids
(Fig. 3)? Boric acid is known to react with 2 equiv of a-hy-
OH
droxycarboxylic acids to give dimeric spiro 4-oxo-1,3,2-di-
a,b CO2C8H17
oxaborolan-2-uide 10,14 which should be more active than 6 21 86
monomeric 2,2-dialkoxy-4-oxo-1,3,2-dioxaborolan-2-uide
9 (Scheme 5). However, equilibrium has been observed be- SH
tween 9 and 10.14 The more active species 10 should exist as 7 24 44
CO2C8H17
a major intermediate in an esterification reaction solution
with a higher molar ratio of a-hydroxycarboxylic acid, while a
Boric acid (10 mol %) was used.
b
the less-active species 9 would be present as a major o-Xylene was used in place of toluene.

B(III) OH B(OH)3 OH
OH (2 mol %) OH (5 mol %)
+ BuOH CO2H CO2C8H17
toluene C8H17OH
Ph CO2H Ph CO2Bu (2 mmol) (2 mmol) 88% yield
(5 mL) + +
reflux, 1 h toluene
Ph CO2H (5 mL) Ph CO2C8H17
(2 mmol) azeotropic 7% yield
Conversion (%) reflux, 16 h
90
OH B(OH)3 OH
80 (5 mol %)
CO2H CO2C8H17
C8H17OH
(2 mmol) (2 mmol) 90% yield
70 + +
toluene
PhCO2H (5 mL) PhCO2C8H17
B(OH)3
60 (2 mmol) azeotropic 1% yield
reflux, 16 h
2a
50
Scheme 4. Boric acid-catalyzed chemoselective esterification of a-hydr-
oxy-a-methylpropanoic acid without excess substrates.
40

30 intermediate in excess alcohol. Based on the experimental

1b
results shown in Figure 3, the reactivity of intermediates
20 with alcohols should increase in the order: 9<2-alkoxy-2-
(N-methylpyridinium-4-yl)-4-oxo-1,3,2-dioxaborolan-2-uides
10 (11 and 12)15<10.

0 Methyl esterification of L-phenylalanine and its N-protected

4:2 2:2 2:6 2:10 2:20
derivatives in methanol was examined in the presence of 2
mandelic acid (mmol) : BuOH (mmol)
(5 mol %) because 2 was the most active catalyst in alcohol
Figure 3. Correlation between the catalytic activity of boron(III) com- solvents (Table 10). Interestingly, N-tosyl-L-phenylalanine
pounds and the molar ratio of mandelic acid and butanol. (entry 1) was much more reactive than L-phenylalanine itself
 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657 8651

R1 O Ganem's amide condensation

O
OH
R1 O O O BH
B– H+ O
R1 CO2H O O (1.2 equiv)
O O H+ R1CO2H + R2R3NH R1CONR2R3
B– 2R2OH THF, –78 °C to rt
R2O OR2 O R1 (1 equiv) (2 equiv)
9 10
very slow very fast R1CO2H
OH
O
R1 CO2R2 BH –H2
fast fast O

R1 O R1 O H2O O O R2R3NH
B
O O –HI O O R1 O O
B– H+ B– 13
OR2 +HI OR2 ?
N+ N+
I– O
11 12 R1CO2H B R1CONR2R3
HO O
Scheme 5. Proposed reaction mechanism. 14

Scheme 6. Ganem’s amide condensation of carboxylic acids with amines

Table 10. Methyl esterification of a-functionalized carboxylic acids using catecholborane as a condensing reagent and a possible catalytic
X 2 (5 mol %) X pathway.
Ph Ph
CO2H MeOH (5 mL) CO2Me
reflux, 20 h was greatly superior to 1 for the amide condensation of steri-
cally demanding carboxylic acids. In addition, we found that
Entry X Yield (%) Entry X Yield (%) Lewis acid-assisted Brønsted acid (LBA)17 4c, which was
1 TsNH 76 5 TfNH 24 prepared from a 1:2 M mixture of boric acid and tetrachloro-
2 CbzNH 61 6 NH2a N.R. catechol, was quite effective for the Ritter reaction to
3 BzNH 45 7 OMeb 71 give amides from the corresponding nitriles and benzylic
4 AcNH 28 8 Mec 28 alcohols.
a
L-Phenylalanine
was not dissolved.
b
a-Methoxyphenylacetic acid was used as a substrate. First, benzo[d][1,3,2]dioxaborol-2-ol 14, which was pre-
c
a-Phenylpropanoic acid was used as a substrate. pared in situ from equimolar mixtures of boric acid and
catechol in toluene under azeotropic reflux conditions, was
and N-carboxyl derivatives. a-Methoxyphenylacetic acid examined as a catalyst (5 mol %) for the dehydrative con-
(entry 7) also showed a similar reactivity to that of N- densation of 4-phenylbutyric acid and benzylamine (entry
tosyl-L-phenylalanine. In contrast, a-phenylpropionic acid was 1, Table 11). As expected, 14 could be used as a dehydration
much less reactive (entry 8). These good results (entries catalyst and was found to be more active than boric acid18
1 and 7) can be understood by the weak coordination of
a-tosylamino and a-methoxy groups to the boron(III) atom. Table 11. Catalytic activities of 1,3,2-dioxaborolan-2-ol derivatives for the
amide condensation of 4-phenylbutyric acids with benzylamine
2.3. Amide condensation reaction of sterically demand- R4 R4
ing carboxylic acids catalyzed by 4,5,6,7-tetrachloro- OH O
R3 + B(OH)3 R3
benzo[d][1,3,2]dioxaborol-2-ol 2 B OH
R toluene R2 O
OH azeotropic
R1 R1
reflux, 3 h
In 1978, Ganem et al. reported that carboxylic acids condense (5 mol %)
with amines via 2-acyloxy-1,3,2-benzodioxaborolane (13) in
the presence of stoichiometric amounts of catecholborane Ph CO2H + H2NBn
Ph CONHBn
under mild conditions (THF, 78  C to rt) (Scheme 6).16 toluene
azeotropic reflux, 1 h
Two equivalents of amine are required because the reaction
proceeds via nucleophilic attack of amine to [13$amine].
Entry Catalyst Conv. (%)
One equivalent of catecholborane is required because ben-
zo[d][1,3,2]dioxaborol-2-ol (14), which is obtained together 1 14 61
with amide, is inert as a condensing reagent under the same 2 4a 93
conditions. Nevertheless, based on a consideration of our re- O O
sults, we envisaged that 14 as well as arylboronic acids such 3 BOH 64
O O
as 1 might serve as dehydrative catalysts under azeotropic
conditions with the removal of water in less-polar solvents O
(Scheme 6). In this section, we report that 4,5,6,7-tetrachloro- 4 BOH 74
O O
benzo[d][1,3,2]dioxaborol-2-ol (4a), which is prepared from
tetrachlorocatechol and boric acid in situ, is sufficiently 5a B(OH)3 31
6a 1 96
active as a catalyst for the dehydrative condensation of equi-
a
molar mixtures of carboxylic acids and amines. Notably, 4a Boric acid and 1 were used instead of 1,3,2-dioxaborolan-2-ol derivatives.
8652 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657

(entry 5), but its activity was still insufficient. Fortunately, Table 13. Amide condensation of various carboxylic acids with amines
4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol 4a was catalyzed by 1 or 4b
much more active than 14 (entry 2). Surprisingly, the cata- 1 or 4b (5 mol %)
R1CO 2H + R2R3NH R1CONR 2R3
lytic activity of 4a was almost the same as that of 1 (entry (2 mmol) (2 mmol)
solvent, azeo tropic reflux
6). According to the Chemicals price catalog (Chemicals,
33rd ed.; Wako Pure Chemical Industries, Ltd.: Japan, Entry Product Solvent Time (h) Yield (%)
2004), 1 is 40 times more expensive than tetrachlorocate- 1 4b
chol. Since boric acid is also available at a rather low price,
4a, which can be prepared from them in situ, is very econom- 1 Ph CONHBn Toluene 0.25 60 41
ical and practical. In contrast, boric acid/oxalic acid and Ph CONBn
boric acid/2-hydroxy-2-methylpropanoic acid were less 2 Toluene 1 42 26
Me
active than 4a, probably due to the instability of their 1,3,2-
3 PhCONHBn o-Xylene 0.5 59 51
dioxaborolan-2-ol structures (entries 3 and 4). 4 PhCONMeBn o-Xylene 1 37 16
CONHBn
Next, the catalytic activities of 4a, 1, and boric acid were 5
Toluene 1 32 62
examined for the dehydrative condensation of cyclohexane- Toluene 5 — 94
carboxylic acid, which is a more sterically demanding carb- CONHBn
oxylic acid than 4-phenylbutyric acid, with benzylamine 6 Toluene 24 8 93
(Table 12). Interestingly, 4a was greatly superior to 1 as a
catalyst (entry 2 vs entry 3). Tetrafluoro- and tetrabromoben- CONHBn Toluene 19 11 55
zo[d][1,3,2]dioxaborol-2-ols also exhibited good catalytic 7
o-Xylene 24 — 99
activities, as well as 4a. Boric acid was almost inert (entry
Toluene 20 5 55
4).18 Furthermore, 4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxa- 8 t-BuCONHBn
o-Xylene 15 — 94
borole (4b), which was isolable,19,20 gave slightly better re-
Toluene 2 25 77
sults than 4a (entry 1). However, 4c, which was prepared in 9
Toluene 5 — 95
Ph CONHBn
situ from a 1:2 M mixture of boric acid and tetrachlorocate- O
chol, was almost inert probably due to the lack of any 10
Toluene 24 15 22
NHBn o-Xylene 20 20 99
hydroxy groups on the boron atom of 4c (entry 5).
Toluene 2 30 32
To explore the generality and scope of the amide condensa- 11 Ph2CHCONHBn
Toluene 11 — 93
tion catalyzed by 4b, the catalytic activities of 4b were com- CONBn o-Xylene 5 47 53
pared with those of 1 in the amide condensation of various 12 Me o-Xylene 19 — 93
substrates in toluene or o-xylene in the presence of
5 mol % of the catalysts. Representative results are shown CONHBn Toluene 5 35 42
13
in Table 13. Although 4b gave inferior results compared to NHBoc Toluene 20 — 91a
1 with sterically small aliphatic and aromatic carboxylic CONHBn o-Xylene 1 32 62
acids (entries 1–4), it still showed adequate catalytic activity 14
o-Xylene 9 — 92
for these substrates. In contrast, 4b was superior to 1 for not
only sterically bulky aliphatic and aromatic carboxylic acids a
Optical purity of the amide was reduced from >99 to 86% ee through
but also functionalized carboxylic acids such as Boc-L-Ala- amide condensation.
OH (entries 5–14). Without exception, amide condensation
was completed within 24 h in the presence of 5 mol % of regeneration step from hydroxyboron compounds to acyl-
4b. The scope of suitable carboxylic acids was extended oxyboron species.
by using 4b as a catalyst instead of 1. In contrast, 1 and 4b
showed a similar trend in catalytic activity with regard to 2.4. Ritter reaction of nitriles with benzylic alcohols
the steric bulkiness of amines (entries 2, 4, and 12). Less- catalyzed by 4c
hindered 4a should have an advantage over 1 at the
In the course of our present study, we were interested in the
utility of 4c as an acid catalyst for the amidation of alcohols
Table 12. Catalytic activities of boron(III) compounds for the dehydrative with nitriles, which is known as the Ritter reaction.21 This
condensation of cyclohexanecarboxylic acid with benzylamine
method works well only under strongly acidic conditions
catalyst (5 mol %) (e.g., cat. concd H2SO4,21,22a cat. BF3$Et2O,22b formic
+ H2NBn
toluene
acid as a solvent,22c and so on) in strongly ionizing solvents,
CO2H azeotropic reflux, 1 h CONHBn which limits its applicability to compounds containing func-
tional groups that are stable toward acid. Although tetra-
Entry Catalysta Conv. (%) chlorocatechol and boric acid were much milder acidic
compounds than traditionally strong acid catalysts, it was
1 4b 62
2 4a 52 expected that their ate complex 4c might synergistically
3 1 32 serve as a Lewis acid-assisted Brønsted acid (LBA).17 The
4 B(OH)3 2 Ritter reaction of several benzylic alcohols with nitriles
5 4c 3 was examined in nitriles in the presence of 5–10 mol % of
a
Compounds 4a and 4c were prepared from boric acid and tetrachloro- 4c under reflux conditions (Table 14). In all cases, the corre-
catechol in situ before the addition of carboxylic acids and amines. sponding amides were isolated in high yield.
 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657 8653

Table 14. Ritter reaction catalyzed by 4c atmosphere of dry nitrogen. For thin-layer chromatography
4c N R2 (TLC) analysis throughout this work, Merck precoated
(5 mol%) R1 TLC plates (silica gel 60 GF254 0.25 mm or silica gel NH2
R1OH O+
R2CN H H F254S 0.25 mm) were used. The products were purified by
reflux Cl Cl column chromatography on silica gel (E. Merck Art. 9385
Cl O O Cl or Fuji Silysia Chemical Ltd. CromatorexÒ NH-DM1020).
B– Microanalyses were performed at the Graduate School
R2CONHR1 Cl O O Cl of Agriculture, Nagoya University. High-resolution mass
Cl Cl spectral analysis (HRMS) was performed at Chemical
Instrument Center, Nagoya University. In experiments that
Entry Time (h) Product Yield (%) required dry solvent, ether, N,N-dimethylformamide
1 a
11 Ph2CHNHCOMe 93 (DMF), and tetrahydorofuran (THF) were purchased from
2 4 Ph2CHNHCOEt 92 Aldrich or Wako as the ‘anhydrous’ and stored over 4 Å
3b 3 Ph2CHNHCOPh 94 molecular sieves. Benzene, hexane, toluene, and dichloro-
4a,b 5 BnNHCOPh 80
methane were freshly distilled from calcium hydride. Other
NHCOPh simple chemicals were analytical-grade and obtained com-
5a,b 3 78
mercially. 1-Ethyl-3-methylimidazolium trifluoromethane-
NHCOEt
sulfonate [emim][OTf] was purchased from Aldrich. The
follwing obtained amides are known compounds: N-benz-
6a 3 84
yl-4-phenylbutanamide3a (Tables 2, 4, 10, and 12), N-benz-
ylcyclohexanecarboxamide3a (Tables 1, 3, 5, 11, and 12),
NHCOEt N-benzyl-N-methyl-4-phenylbutanamide4 (Tables 3, 5, and
7 3 93 12), N-benzyl-2-methoxy-2-phenylacetamide23 (Tables 3
Ph
and 5), N-benzyl-2-hydroxyl-2-phenylacetamide3a (Table
3), 2-methoxy-N-phenyl-2-phenylacetamide24 (Table 3),
NHCOEt
N-benzyl-1-adamantanecarboxamide4 (Tables 3 and 13),
8 3 96 (E)-N-benzylcinnamide25 (Table 3), N-benzylbenzamide26
F F (Tables 3, 13, and 14), N-benzyl-p-cyanobenzamide27
a
(Tables 3 and 5), (S)-methyl 2-(4-methylphenylsulfon-
Compound 4c (10 mol %) was used. amido)-3-phenylpropanoate (Table 10),28 (S)-methyl 2-(benz-
b
The reaction was carried out at 120  C.
yloxycarbonylamino)-3-phenylpropanoate (Table 10),29
(S)-methyl 2-benzamido-3-phenylpropanoate (Table 10),30 (S)-
3. Conclusion methyl 2-acetamido-3-phenylpropanoate (Table 10),31
methyl 2-methoxy-2-phenylacetate (Table 10),32 methyl 2-
In summary, N-alkyl-4-boronopyridinium salts are ther- phenylpropanoate (Table 10),33 N-benzyl-N-methylbenz-
mally stable and reusable catalysts for not only the amida- amide6 (Table 13), N-benzyl-2-ethylbutanamide6 (Table
tion but also the esterification of a-hydroxycarboxylic 13), N-benzyl-2-propylpentanamide6 (Table 13), N-benzyl-
acids in excess alcohols. Boric acid is also an effective cat- pivalamide34 (Table 13), N-benzyl-2-phenylpropanamide35
alyst for not only the amidation18 but also the esterification (Table 13), N-benzyl-2,2-diphenylacetamide36 (Table 13),
of equimolar mixtures of a-hydroxycarboxylic acids and N-benzyl-N-methylcyclohexanecarboxamide6 (Table 13),
alcohols. Furthermore, catecholborane derivatives such as (S)-tert-butyl 1-(benzylamino)-1-oxopropan-2-ylcarbamate37
4a and 4b are economically and practically useful catalysts (Table 13), N-benzyl-2-methylbenzamide26 (Table 13),
for the amidation of sterically demanding carboxylic acids N-benzhydrylacetamide38 (Table 14), N-benzhydrylpropion-
and 4c is useful as a LBA catalyst for the Ritter reaction. amide22c (Table 14), N-benzhydrylbenzamide22c (Table 14),
N-(4-methylbenzyl)benzamide39 (Table 14), N-[di(p-tolyl)-
methyl]propionamide6 (Table 14), N-[naphthalen-2-
4. Experimental yl(phenyl)methyl]propionamide6 (Table 14), N-[di(p-fluoro-
phenyl)methyl]propionamide6 (Table 14). The following
4.1. General obtained esters are known compounds: methyl 2-hydroxy-
2-phenylacetate26 (Tables 6 and 7), isobutyl 2-hydroxy-2-
Infrared (IR) spectra were recorded on a JASCO FT/IR 460 phenylacetate5 (Tables 6–8), methyl 2-hydroxy-3-phenyl-
plus spectrometer. 1H NMR spectra were measured on a propanoate40 (Table 7), methyl 2-hydroxy-2-methylpropa-
Varian Gemini-2000 spectrometer (300 MHz) at ambient noate26 (Table 7), ethyl 2-hydroxy-2-phenylacetate26
temperature. Data were recorded as follows: chemical shift (Tables 6 and 7), isopropyl 2-hydroxy-2-phenylacetate11
in parts per million from internal tetramethylsilane on the (Tables 6 and 7), 2-hydroxyethyl 2-hydroxy-2-phenylace-
d scale, multiplicity (s¼singlet; d¼doublet; t¼triplet; tate5 (Tables 6 and 7), (S)-dimethyl 2-hydroxysuccinate26
m¼multiplet), coupling constant (Hz), integration, and (Table 7), (S)-diethyl 2-hydroxysuccinate41 (Table 7),
assignment. 13C NMR spectra were measured on Varian (2R,3R)-diethyl 2,3-dihydroxysuccinate26 (Table 7), iso-
Gemini-2000 (75 MHz) spectrometer. Chemical shifts butyl 2-hydroxybenzoate26 (Table 7), 4-hydroxy-3-(iso-
were recorded in parts per million from the solvent reso- butoxycarbonyl)benzoic acid5 (Table 7), (S)-methyl 2-
nance employed as the internal standard (deuterochloroform (benzyloxycarbonylamino)-3-hydroxypropanoate26 (Table
at 77.00 ppm). Melting points were determined using a 7), (2S,3R)-methyl 2-(benzyloxycarbonylamino)-3-hydroxy-
Yanaco MP-J3. All experiments were carried out under an butanoate26 (Table 7), butyl 2-hydroxy-2-phenylacetate5
8654 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657

(Fig. 3), octyl 2-hydroxy-2-phenylacetate5 (Table 9), octyl 3030, 1636, 1558, 1456, 1208, 1123, 932, 843, 799, 748,
2-hydroxy-2-methylpropanoate5 (Table 9 and Scheme 2), 683 cm1; 1H NMR (DMSO-d6 with 1 drop of D2O,
octyl 2-hydroxy-2-phenylpropanoate5 (Table 9), (+)- 300 MHz) d 4.16 (s, 3H), 7.51 (d, J¼6.3 Hz, 2H), 8.43 (d,
(2R,3R)-dioctyl 2,3-dihydroxysuccinate42 (Table 9), cyclo- J¼6.3 Hz, 2H); 13C NMR (DMSO-d6 with 5 drops of
dodecyl 2-hydroxy-2-methylpropanoate5 (Table 9), octyl D2O, 300 MHz) d 47.9, 131.4 (2C), 143.3 (2C), and one
2-hydroxybenzoate5 (Table 9), octyl 4-phenylbutyrate43 carbon was not observed. Anal. Calcd for C72H84B12
(Scheme 2), and octyl benzoate44 (Scheme 2). I8N12O14$10H2O: C, 32.43; H, 3.93; N, 6.30; I, 38.07.
Found: C, 32.15; H, 3.71; N, 6.20; I, 38.44.
4.2. Preparation of 4-(5,5-dimethyl-1,3,2-dioxaborinan-
2-yl)pyridine 4.5. X-ray crystallographic analysis of [2]12

A flame-dried, 100-mL round-bottom flask fitted with a Tef- Crystal data: C72H104B12N12O24I8, M¼2666.59, crystal di-
lon-coated magnetic stirring bar was charged with 4-pyr- mensions 0.400.400.30 mm3, monoclinic, space group
idineboronic acid (8) (1.23 g, 10 mmol) and neopentyl P21/n, a¼17.136(4), b¼14.073(3), c¼21.289(5) Å, V¼
glycol (1.04 g, 10 mmol) in 1,4-dioxane (50 mL). This white 5115.6(19) Å3, Z¼2, Dc¼1.731 g/cm3, m¼2.495/mm, T¼
suspension was brought to reflux with the removal of water 223 K. X-ray crystallographic analysis was performed with
with molecular sieves 4 Å for 12 h to be a homogeneous a Bruker SMARTAPEX diffractometer (graphite monochro-
solution. The resulting mixture was cooled to ambient tem- mator, Mo Ka radiation, l¼0.71073 Å). The structure was
perature and bulk solvent was removed in vacuo to afford solved by direct methods and expanded using Fourier tech-
4-pyridineboronic acid neopentyl glycol ester (1.92 g, niques. Reflections 13,391 were independent and unique,
10 mmol) as white solid in quantitative yield. IR (KBr) and 10,822 with I>2s(I) (2qmax¼29.16 ) were used for the
3436, 2943, 2821, 1620, 1423, 1215, 1117, 1035, 768, solution of the structure. R¼0.0438 and Rw¼0.1235.
736, 674, 626 cm1; 1H NMR (CD3CN, 300 MHz) d 0.98
(s, 6H), 3.76 (s, 4H), 7.57 (d, J¼5.7 Hz, 2H), 8.55(d, Crystallographic data have been deposited with Cambridge
J¼5.7 Hz, 2H); 13C NMR (CD3CN, 75 MHz) d 21.6 (2C), Crystallographic Data Centre: Deposition number CCDC-
67.5, 72.3 (2C), 128.6 (2C), 149.9 (2C), and one carbon 27344 for compound [2]12. Copies of the data can be ob-
was not observed. HRMSFAB (m/z): [M+H]+ calcd for tained free of charge via http//www.ccdc.cam.ac.uk/conts/
C10H15NO2, 192.1198; Found, 192.1197. retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK;
4.3. Preparation of 4-borono-N-methylpyridinium fax: +44 1223 336033; e-mail: [email protected]).
iodide (2)45
4.6. Preparation of N-polystyrene-bound 4-borono-
4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)pyridine (1.92 g, pyridinium salts 3
10 mmol) was suspended in acetonitrile (50 mL) and added
methyl iodide (3.11 mL, 50 mmol). The mixture was brought A mixture of 4-(haloalkyl)polystrene resin crosslinked with
to heat at reflux for 6 h followed by removal of acetonitrile in divinyl benzene (2.4 mmol) and 4-pyridineboronic acid neo-
vacuo to afford 4-borono-N-methylpyridinium iodide neopen- pentyl glycol ester (990 mg, 4.8 mmol) in acetonitrile
tyl glycol ester as yellow solid in quantitative yield. The result- (20 mL) was heated at reflux for 2 days. After the resultant
ing yellow solid was added to a mixture of acetone (30 mL) mixture was cooled to ambient temperature, the resin was col-
and water (30 mL). After this light yellow solution was stirred lected by filtration and washed with THF, DMF, and Et2O.
at room temperature for 1 day, acetone was removed in vacuo, The resin was added to a mixture of THF (15 mL) and water
and the aqueous solution was washed with Et2O until neopen- (5 mL). This mixture was stirred at room temperature for
tyl glycol was extracted completely. The aqueous solution 1 day. The resultant resin was collected by filtration and
was concentrated and resulting yellow solid was precipitated washed with THF, water, DMF, EtOAc, hexane, and Et2O,
from methanol/Et2O to give 2 (2.26 g, 9.0 mmol, 90% yield and dried at 50  C under reduced pressure for 12 h to give 3.
from 7). IR (KBr) 3347, 3026, 1637, 1461, 1404, 1344,
1272, 1012, 853, 678, 627 cm1; 1H NMR (DMSO-d6 with Compound 3a:45 Merrifield resin (ca. 1.0 mmol-Cl/g, 400–
1 drop of D2O, 300 MHz) d 4.32 (s, 3H), 8.24 (d, J¼6 Hz, 500 mm, crosslinked with 1% divinylbenzene) purchased
2H), 8.88 (d, J¼6 Hz, 2H); 13C NMR (DMSO-d6 with 1 from Fluka was used as a polymer-support; 0.74 mmol-B/g
drop of D2O, 75 MHz) d 48.3, 132.0 (2C), 144.3 (2C), and (estimated based on nitrogen content as determined by ele-
one carbon was not observed. Anal. Calcd for C6H9O2BNI: mental analysis). IR (KBr) 3409, 3025, 2923, 1635, 1602,
C, 27.21; H, 3.43. Found: C, 27.02, H, 3.47. 1493, 1452, 757, 698, 538 cm1. Anal. Found: C, 84.21;
H, 7.51; N, 1.04.
4.4. Preparation of dodecamer [2]12
Compound 3b: 4-(2-Bromoethyl)polystyrene resin (ca.
A dry, 5-mL round-bottom flask equipped with a Teflon- 0.8–1.2 mmol-Br/g, 500–560 mm, crosslinked with 1% di-
coated magnetic stirring bar was charged with 2 (3 mmol) vinylbenzene) purchased from Fluka was used as a polymer-
and DMF (3 mL). The mixture was heated at 120  C for support; 0.81 mmol-B/g (estimated based on nitrogen
1 h to form yellow precipitate. After the resultant mixture content as determined by elemental analysis). Anal. Found:
was cooled to ambient temperature, the precipitate was col- C, 82.00; H, 7.56; N, 1.14; Br, 6.52.
lected by filtration and washed with DMF several times to
obtain white solid. The white solid was recrystallized from Compound 3c: 4-(2-Bromoethyl)polystyrene resin (ca.
water to get [2]12 as an orange crystal. IR (KBr) 3465, 0.8–1.2 mmol-Br/g, 500–560 mm, crosslinked with 1%
 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657 8655

divinylbenzene) purchased from Fluka was used as a poly- After the reaction was completed, the resulting mixture
mer-support; 0.48 mmol-B/g (estimated from weight differ- was cooled to ambient temperature and filtered. Compound
ence). Anal. Found: C, 77.01; H, 6.78; N, 1.47. 3a was washed with 1 M HCl aqueous solution and ethyl
acetate repeatedly, and was used directly in the next reaction
Compound 3d: 4-(4-Bromobutyl)polystyrene resin without further purification. On the other hand, the desired
(2.8 mmol-Br/g, 200–400 mesh, crosslinked with 2% di- ester was isolated from the combined filtrates by column
vinylbenzene) purchased from Novabiochem was used as chromatography on silica gel.
a polymer-support; 1.47 mmol-B/g (estimated based on
nitrogen content as determined by elemental analysis). Anal. 4.11. General procedure for the esterification of
Found: C, 65.06; H, 6.93; N, 2.06. equimolar mixtures of carboxylic acids and
alcohols catalyzed by B(OH)3 (Table 9)
4.7. General procedure for the direct amide condensa-
tion of equimolar mixtures of carboxylic acids and A dry, 10-mL round-bottom flask equipped with a Teflon-
amines catalyzed by 2 (Tables 1–3) coated stirring bar and a Dean–Stark apparatus surmounted
by a reflux condenser was charged with hydroxycarboxylic
A dry, 20-mL round-bottom flask equipped with a Teflon- acids (2 mmol), alcohols (2 mmol), and B(OH)3 (6.2 mg,
coated magnetic stirring bar and a Dean–Stark apparatus sur- 0.1 mmol) in toluene (5 mL). The mixture was brought to
mounted by a reflux condenser was charged with carboxylic reflux with the removal of water. After the reaction was
acid (2 mmol), amine (2 mmol), and 2 (25 mg, 0.1 mmol) in complete, the resulting mixture was cooled to ambient
[emim][OTf] (1 mL) and toluene (5 mL). The mixture was temperature and washed with sodium hydrogen carbonate,
brought to reflux with the removal of water. After several and the product was extracted with ethyl acetate. The
hours, the resulting mixture was cooled to ambient temper- organic layers were dried over magnesium sulfate. The
ature and a colorless toluene layer was separated from a yel- solvents were evaporated, and the residue was purified by
low ionic liquid layer by simple extraction with Et2O, and column chromatography on silica gel to give the desired
concentrated in vacuo. The desired amide was isolated ester.
from crude products by column chromatography on silica
gel. On the other hand, 2 that remained in [emim][OTf] Octyl 2-mercaptopropanoate (entry 7): IR (film) 2927, 2856,
was reused in the next reaction without further purification. 1737, 1455, 1327, 1173, 1073 cm1; 1H NMR (CDCl3,
300 MHz) d 0.88 (t, J¼6.6 Hz, 3H), 1.20–1.42 (m, 10H),
4.8. General procedure for the direct amide condensa- 1.53 (d, J¼7.2 Hz, 3H), 1.61–1.68 (m, 2H), 2.15 (d,
tion of equimolar mixtures of carboxylic acids and J¼8.1 Hz, 1H), 3.50 (dq, J¼7.2, 8.1 Hz, 1H), 4.06–4.19
amines catalyzed by 3a (Tables 4 and 5). (m, 2H); 13C NMR (CDCl3, 75 MHz) d 13.9, 21.0, 22.5,
25.7, 28.3, 29.0 (2C), 31.6, 35.6, 65.4, 173.5. Anal. Calcd
A dry, 5-mL round-bottom flask equipped with a Teflon- for C11H22O2S: C, 60.51; H, 10.16. Found: C, 60.48; H,
coated stirring bar and a Dean–Stark apparatus surmounted 10.20.
by a reflux condenser was charged with carboxylic acid
(1 mmol), amine (1 mmol), and 3a (135 mg, 0.74 mmol-B/ 4.12. In situ preparation of 4,5,6,7-tetrachlorobenzo-
g, 0.1 mmol) in toluene (5 mL). The mixture was brought [d][1,3,2]dioxaborol-2-ol (4a) (Tables 11 and 12)
to reflux with the removal of water. After several hours,
the resulting mixture was cooled to ambient temperature A dry, 20-mL round-bottom flask equipped with a Teflon-
and filtered. Compound 3a was washed with 1 M HCl aque- coated magnetic stirring bar and a Dean–Stark apparatus sur-
ous solution and ethyl acetate repeatedly, and was reused in mounted by a reflux condenser was charged with B(OH)3
the next reaction without further purification. On the other (6.1 mg, 0.10 mmol) and tetrachlorocatechol (25 mg,
hand, the desired amide was isolated from the combined 0.10 mmol) in toluene (10 mL). The mixture was brought
filtrates by column chromatography on silica gel. to heat at azeotropic reflux with the removal of water for
3 h to prepare a solution of 4a. After 3 h, B(OH)3 [11B
4.9. General procedure for the esterification of hydroxy- NMR (DMSO-d6, 96 MHz) d 20] was dissolved completely,
carboxylic acids in alcohols catalyzed by 2 (Table 7) and the resulting solution was used as catalyst directly in the
amide condensation without further purification. 11B NMR
To a stirring solution of hydroxycarboxylic acids (2 mmol) (DMSO-d6, 96 MHz) d 8.7; 13C NMR (DMSO-d6,
in alcohol (5 mL) was added 2 (26.5 mg, 0.1 mmol) in one 75 MHz) d 119.7 (2C), 121.4 (2C), 143.8 (2C).
portion and the mixture was dissolved soon. The solution
was stirred at room temperature or was heated to reflux. Af- 4.13. Preparation of 4,5,6,7-tetrachlorobenzo[d][1,3,2]-
ter the reaction was complete, excess alcohol was removed dioxaborole (4b) (Tables 12 and 13)
in vacuo, and the residue was purified by column chromato-
graphy on silica gel to give the desired ester. Tetrachlorocatechol (2.5 g, 10 mmol) in Et2O (10 mL) was
added slowly to a stirred solution of BH3$SMe2 (1.2 mL,
4.10. General procedure for the esterification of hydroxy- 12 mmol, 10 M) in ether (10 mL) at ambient temperature.
carboxylic acids in alcohols catalyzed by 3a (Table 8) Gas evolution began immediately. After a few minutes, all
volatile components were removed in vacuo to yield almost
To a stirring solution of hydroxycarboxylic acids (1 mmol) pure light yellow solid, which after sublimation at
in alcohol (2.5 mL) was added 3a (135 mg, 0.1 mmol, 100  C/1 Torr gave 2.2 g of pure 4b (83% yield) as clusters
0.74 mmol-B/g), and the mixture was brought to reflux. of very fine needles. Mp 95–100  C; 11B NMR (CDCl3,
8656 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657

96 MHz) d 29.1; 13C NMR (CDCl3, 75 MHz) d 117.0 (2C), Ohara, S.; Yamamoto, H. Org. Synth. 2002, 79, 176–185; (d)
127.8 (2C), 143.7 (2C). Maki, T.; Ishihara, K.; Yamamoto, H. Synlett 2004, 1355–
1358; (e) Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett
4.14. Typical procedure for the amide condensation 2001, 1371–1374.
reaction of an equimolar mixture of carboxylic acids 4. Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5043–
and amines catalyzed by 4b (Table 13) 5046.
5. Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5047–
A dry, 20-mL round-bottom flask equipped with a Teflon- 5050.
coated magnetic stirring bar and a Dean–Stark apparatus sur- 6. Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 1431–
mounted by a reflux condenser was charged with carboxylic 1434.
acids (2.0 mmol), amines (2.0 mmol), and 4b (26 mg, 7. (a) Ohara, S.; Ishihara, K.; Yamamoto, H. The 77th Spring
0.10 mmol, 5.0 mol %) in toluene or o-xylene (10 mL). Meeting of Chem. Soc. Jpn., 2000; (b) Ishihara, K.;
The mixture was brought to heat at azeotropic reflux with Yamamoto, H. Jpn. Kokai Tokkyo Koho JP 270939, 2001
the removal of water. After the reaction was completed, (2001-10-02); Application: JP 87495, 2000 (2000-03-27).
the resulting mixture was cooled to ambient temperature 8. Latta, R.; Springsteen, G.; Wang, B. Synthesis 2001, 1611–
and washed with both aqueous solutions of ammonium chlo- 1613.
ride and sodium hydrogen carbonate, and the product was 9. (a) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57,
extracted with ethyl acetate. The combined organic layers 9813–9816; (b) Bouillon, A.; Lancelot, J.-C.; de Oliveria
were dried over magnesium sulfate. The solvent was evapo- Santos, J. S.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
rated, and the residue was purified by column chromato- 2003, 59, 10043–10049; (c) Gros, P.; Doudouth, A.; Fort, Y.
graphy on silica gel to give the desired amides. Tetrahedron Lett. 2004, 45, 6239–6241.
10. According to the report by Wang and co-workers,8 the amide
4.15. Typical procedure for Ritter reaction catalyzed by condensation of less-reactive benzoic acid (1 equiv) with benz-
4c (Table 14) ylamine (1.2 equiv) gave the product in 92% isolated yield in
the presence of 1 mol % of 3-pyridineboronic acid or 5 in
A dry, 10-mL round-bottom flask equipped with a Teflon- toluene. However, we could not duplicate Wang’s results, and
coated magnetic stirring bar and a reflux condenser was obtained the amide in less than 10% yield under the same
charged with B(OH)3 (6.2 mg, 0.10 mmol), tetrachlorocate- conditions.
chol (50 mg, 0.20 mmol), and benzylic alcohols (2.0 mmol) 11. Houston, T. A.; Wilkinson, B. L.; Blanchfield, J. T. Org. Lett.
in nitriles (5 mL). The mixture was brought to reflux. After 2004, 6, 679–681.
the reaction was completed, the resulting mixture was 12. Tertiary alcohols were not condensed with a-hydroxycarb-
cooled to ambient temperature and washed with an aqueous oxylic acids.
solution of sodium hydrogen carbonate, and the product was 13. After the reaction, 3a must be washed with 1 M HCl aqueous
extracted with ethyl acetate. The combined organic layers solution. Without this manipulation, the catalytic activity of
were dried over magnesium sulfate. The solvent was evapo- 3a is diminished.
rated, and the residue was purified by column chromato- 14. (a) Babcock, L.; Pizer, R. Inorg. Chem. 1980, 19, 56–61; (b)
graphy on silica gel to give the desired amides. Lamande, L.; Boyer, D.; Munoz, A. J. Organomet. Chem.
1987, 329, 1–29; (c) Bello-Ramırez, M. A.; Martınez,
LBA 4c: 11B NMR (DMSO-d6, 96 MHz) d 14.7; 13C NMR M. E. R.; Flores-Parra, A. Heteroat. Chem. 1993, 4, 613; (d)
(DMSO-d6, 75 MHz) d 111.7 (4C), 120.3 (4C), 147.6 (4C). Pizer, R.; Ricatto, P. J. Inorg. Chem. 1994, 33, 2402–2406.
15. It is not clear whether 11 or 12 is the more active intermediate.
16. Collum, D. B.; Chen, S.; Ganem, B. J. Org. Chem. 1978, 43,
Acknowledgements 4393–4394.
17. (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
We thank Dr. M. Hatano (Nagoya University) for performing 1561–1562; (b) Ishihara, K.; Miyata, M.; Hattori, K.; Tada,
X-ray single-crystal analysis. Financial support for this pro- T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520–
ject was provided by SORST and Research for Promoting 10524; (c) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am.
Technological Seeds from JST, the 21st Century COE Pro- Chem. Soc. 1996, 118, 3049–3050; (d) Ishihara, K.; Kondo,
gram of MEXT, and the Iwatani Naoji Foundation. T.M. S.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62,
also acknowledges a JSPS Fellowship for Japanese Junior 3026–3027; (e) Ishihara, K.; Kurihara, H.; Matsumoto, M.;
Scientists. Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920–6930.
18. (a) Tang, P. Org. Synth. 2005, 81, 262–272; (b) Arnold, K.;
Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.; Whiting,
References and notes A. Adv. Synth. Catal. 2006, 348, 813–820. In this paper,
Whiting and co-workers reported that o-(N,N-diisopropyl-
1. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and aminomethyl)benzeneboronic acid was more effective for the
Practice; Oxford University: Oxford, 1988. amide condensation reaction of benzoic acid than boric acid
2. Benz, G. Comprehensive Organic Synthesis; Trost, B. M., and 3,4,5-trifluorobenzeneboronic acid.
Fleming, I., Eds.; Pergamon: New York, NY, 1991; Vol. 6, 19. 4,5,6,7-Tetrafluoro- and 4,5,6,7-tetrabromobenzo[d][1,3,2]-
p 323. dioxaborol-2-ols could not be isolated by distillation tech-
3. (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, niques.
61, 4196–4197; (b) Ishihara, K.; Ohara, S.; Yamamoto, H. 20. Lang, A.; N€ oth, H.; Thomann-Albach, M. Chem. Ber./Recueil.
Macromolecules 2000, 33, 3511–3513; (c) Ishihara, K.; 1997, 130, 363–369. In this paper, 4b was prepared from
 T. Maki et al. / Tetrahedron 63 (2007) 8645–8657 8657

3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione and BH3$THF. 33. Page, P. C. B.; McKenzie, M. J.; Allin, S. M.; Klair, S. S.
We prepared 4b from tetrachlorocatechol and BH3$SMe2 in Tetrahedron 1997, 53, 13149–13164.
Et2O because THF was decomposed due to the strong Lewis 34. Kita, Y.; Akai, S.; Ajimura, N.; Yoshigi, M.; Tsugoshi, T.;
acidity of 4b under the distillation conditions. Yasuda, H.; Tamura, Y. J. Org. Chem. 1986, 51, 4150–
21. (a) Benson, F. R.; Ritter, J. J. J. Am Chem. Soc. 1947, 71, 4128– 4158.
4129; (b) Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213– 35. Tsuji, Y.; Ohsumi, T.; Kondo, T.; Watanabe, Y. J. Organomet.
325. Chem. 1986, 309, 333–344.
22. (a) Reddy, K. L. Tetrahedron Lett. 2003, 44, 1453–1455; (b) 36. Pop, I. E.; Deprez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62,
Firouzabadi, H.; Sardarian, A. R.; Badparva, H. Synth. 2594–2603.
Commun. 1994, 24, 601–607; (c) Gullickson, G. C.; Lewis, 37. Kim, J.-M.; Wilson, T. E.; Norman, T. C.; Schultz, P. G.
D. E. Synthesis 2003, 681–684. Tetrahedron Lett. 1996, 37, 5309–5312.
23. Hoffman, R. V.; Nayyar, N. K. J. Org. Chem. 1995, 60, 7043– 38. Gullickson, G. C.; Lewis, D. E. Aust. J. Chem. 2003, 56, 385–
7046. 388.
24. Prager, R. H.; Smith, J. A. Aust. J. Chem. 1995, 48, 217–226. 39. Kang, Y.-J.; Chung, H.-A.; Kim, J.-J.; Yoon, Y.-J. Synthesis
25. Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling, S. 2002, 733–738.
Tetrahedron 2000, 56, 979–988. 40. Commercially available from Fluka.
26. Commercially available from Aldrich. 41. Commercially available from Tokyo Kasei Kogyo Co., Ltd.
27. Ockey, D. A.; Dotson, J. L.; Struble, M. E.; Stults, J. T.; (TCI).
Bourell, J. H.; Clark, K. R.; Gadek, T. R. Bioorg. Med. 42. van Nunen, J. L.; Folmer, B. F. B.; Nolte, R. J. M. J. Am. Chem.
Chem. 2004, 12, 37–41. Soc. 1997, 119, 283–391.
28. Ordoñez, M.; De la Cruz-Cordero, R.; Fernandez-Zertuche, 43. Rees, G. D.; Jenta, T. R. J.; Nascimento, M. G.; Catauro, M.;
M.; Muñoz-Hernandez, M. A.; Garcıa-Barradas, O. Robinson, B. H.; Stepheson, G. R.; Olphert, R. D. G. Indian
Tetrahedron: Asymmetry 2004, 15, 3035–3043. J. Chem., Sect. B 1993, 32B, 30.
29. Kreuzfield, H.-J.; D€obler, C.; Krause, H. W.; Facklam, C. 44. Bram, G.; F-Khan, T.; Geraghty, N. Synth. Commun. 1980,
Tetrahedron: Asymmetry 1993, 4, 2047–2051. 10, 279–289.
30. Tanaka, K.; Ahn, M.; Watanabe, Y.; Fuji, K. Tetrahedron: 45. Since 2006, 2 and 3a have been commercially available from
Asymmetry 1996, 7, 1771–1782. Wako Pure Chemical Industries, Ltd., Japan, as N-methyl-4-
31. Kunishima, M.; Kawachi, C.; Hiroki, K.; Terao, K.; Tani, S. pyridineboronic acid iodide (130-15181 for 100 mg, 132-15185
Tetrahedron 2001, 57, 1551–1558. for 500 mg) and polystyrene-bound N-methyl-4-pyridineboronic
32. Martin, C. W.; Lund, P. R.; Rapp, E.; Landgrebe, J. A. J. Org. acid chloride (165-22241 for 100 mg, 161-22243 for 500 mg),
Chem. 1978, 43, 1671–1676. respectively.