Convenient amidation of carboxyl group of carboxyphenylboronic acids

Article abstract of DOI:10.1515/chempap-2015-0245

The use of catalysts in the activation of carboxyl groups towards nucleophilic attack and the protection of other functional groups by suitable protecting groups are standard and necessary procedures in amide bond formation. In contrast to the usual metho

Full text of DOI:10.1515/chempap-2015-0245

Chemical Papers 70 (5) 658–662 (2016)
DOI: 10.1515/chempap-2015-0245
SHORT COMMUNICATION
Convenient amidation of carboxyl group
of carboxyphenylboronic acids
Julia Nowak-Jary*
Faculty of Biological Sciences, University of Zielona Góra, ul. Szafrana 1, 65-516 Zielona Góra, Poland
Received 13 August 2015; Revised 18 October 2015; Accepted 21 October 2015
The use of catalysts in the activation of carboxyl groups towards nucleophilic attack and the
protection of other functional groups by suitable protecting groups are standard and necessary pro-
cedures in amide bond formation. In contrast to the usual methods, various new compounds, amides
of APTES ((3-aminopropyl)triethoxysilane, 3-triethoxysilylpropylamine) and carboxyphenylboronic
acids, as well as the amides of aniline and carboxyphenylboronic acids, were obtained in good yields
by a one-step synthesis under mild conditions without using any coupling reagents or additional
catalysts.
c
ꢀ 2015 Institute of Chemistry, Slovak Academy of Sciences
Keywords: carboxyphenylboronic acids, amides, APTES, aniline, boronobenzanilides, amidation
reaction
No simple general procedure for direct produc-
tion of amides from free carboxylic acids and amines
has yet been introduced. The thermal dehydration re-
action between carboxylic acids and amines leading
to amide bond formation occurs at very high tem-
peratures (160◦C and higher) (Jursic & Zdravkovski,
1993). One widely used method uses acid chlorides as
electrophiles that react with the amines; limitations
of this method are due to the instability of many acid
chlorides typically requiring hazardous reagents for
their preparation. Another common means of forming
amide bonds involves coupling reagents, such as car-
bodiimides or phosphonium salts, to activate and de-
hydrate carboxylic acid (Montalbetti & Falque, 2005).
A widely known method involving coupling reagent,
especially common in peptide synthesis, is the N-
hydroxysuccinimide (HOSu) active ester method (An-
derson et al., 1964) which uses dicyclohexylcarbodi-
imide (DCC) as the coupling reagent. However, 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
is superior to DCC because of its high solubility in
water and organic solvents, such as MeOH, CH2Cl2,
and THF, and its functional simplicity (Sheehan et al.,
1961).
The use of small amount (10 mole %) of boric
acid and phenylboronic acid (PBA) (Mylavarapu
et al., 2007) as well as their derivatives as cata-
lysts in amidation reactions has also been reported.
The highest yields (60–95 %) of products were ob-
tained using the following PBA derivatives as cata-
lysts: a series of fluorophenylboronic acids and 3,4-
chlorophenylboronic acid (Tam et al., 2015), bro-
mophenylboronic and iodophenylboronic acid (Al-
Zoubi et al., 2008), tris(2,2,2-trifluoroethyl) borate
(Lanigan et al., 2013), and 2-furanylboronic, 3-
cyanophenylboronic and 2-thiophenylboronic acids
(Tam et al., 2015). All the above-mentioned com-
pounds were added as catalysts to the reaction mix-
ture containing carboxylic acid and an amine. The
PBA derivatives can also be applied in their immo-
bilized form (Gu et al., 2014). Noda and Bode (2014)
described a method, where acylboronate MIDA esters
(MIDA = N-methyliminodiacetic acid) are substrates
for the amidation reaction. In such compounds, the
boron atom of the MIDA ester is substituted by the
nitrogen atom of O-methylhydroxylamine. It is worth
noting that the nucleophilic attack on the carbon atom
of the carboxylic group on the aromatic ring is usually
*Corresponding author, e-mail: J.Nowak-Jary@wnb.uz.zgora.pl
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J. Nowak-Jary/Chemical Papers 70 (5) 658–662 (2016)
659
Fig. 1. Chemical structures of 3-{[3-(triethoxysilyl)propyl]carbamoyl}phenylboronic acid (I), 4-{[3-(triethoxysilyl)propyl]carbamoyl}
phenylboronic acid (II), 3-(phenylcarbamoyl)phenylboronic acid (III), and 4-(phenylcarbamoyl)phenylboronic acid (IV ).
Fig. 2. Synthesis of amide I using compound V as the initial substrate and dicarbodiimides as coupling reagents. Reaction con-
ditions: method A: i) DCC/HOSu, THF, 0◦C; method B: ii) EDC, MeOH, 25◦C; iii) APTES, MeOH, 25◦C; iv) aq.
HCl, 25◦C; v) aq. NaOH, THF, 25◦C. Compound II was synthesized in a similar manner at the same conditions using
4-carboxyphenylboronic acid MIDA ester as the initial substrate.
hampered because of the higher electron density.
In this work, which is a part of a broader re-
search concerning immobilization of carboxyphenyl-
boronic acids (CPBA) on magnetic nanoparticles
of Fe3O4, a convenient method for the synthesis
of CPBA amides is reported. The following com-
pounds were synthesized and characterized: 3-{[3-
(triethoxysilyl)propyl]carbamoyl}phenylboronic acid
(I ), 4-{[3-(triethoxysilyl)propyl]carbamoyl}phenylbo-
ronic acid (II ), 3-(phenylcarbamoyl)phenylboronic
acid (III ), and 4-(phenylcarbamoyl)phenylboronic
acid (IV ) (Fig. 1).
First, the amides containing (3-aminopropyl)tri-
ethoxysilane (3-triethoxysilylpropylamine) (APTES)
were synthesized by two common methods: using DCC
as the coupling reagent via active ester formation
(method A); and using EDC as a reagent directly cou-
pling carboxylic acid and amines (method B) (Fig. 2).
3-Carboxyphenylboronic acid MIDA ester (IUPAC
name: 3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-
2-yl)benzoic acid) (V ) and 4-carboxyphenylboronic
acid MIDA ester (IUPAC name: 4-(6-methyl-4,8-
dioxo-1,3,6,2-dioxazaborocan-2-yl)benzoic acid) (both
esters are commercially available from Sigma–Aldrich)
were used as initial substrates for the preparation of
compounds I and II, respectively. Substrates with pro-
tected hydroxyl groups were used in order to avoid
possible side reactions.
Final products in both cases were purified by
column chromatography using ethyl acetate/hexane
(ϕr = 1 : 8) as the eluent. The achieved overall yields
of I and II (41 % and 43 %, respectively (method A)
and 24 % and 26 %, respectively (method B)) were
not satisfactory. Therefore, application of the reac-
tions shown in Fig. 2 (methods A and B) to synthesize
compounds III and IV was abandoned.
In recent years, reports on PBA as a capable cat-
alyst in the amide bond formation process have oc-
curred (Lundberg et al., 2014). PBA forms mixed
anhydrides with carboxylic acids activating thereby
the carboxyl moiety by reducing the electron density
at the carbonyl function. This information was the
basis of the assumption that two molecules of car-
boxyphenylboronic acid can form mixed anhydrides
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J. Nowak-Jary/Chemical Papers 70 (5) 658–662 (2016)
◦
˚
Fig. 3. Direct synthesis of amideI without the use of catalyst. Reaction conditions: i) toluene/MeOH, 4 A molecular sieves, 60 C,
1 h; ii) APTES, 60◦C, 24 h; iii) 0.5 M aqueous HCl, 25◦C. Compound II was synthesized in a similar manner under the
same reaction conditions using 4-CPBA as the initial substrate.
Table 1. Synthesis of I and II by direct amidation of CPBA
removed by filtration using a glass funnel with filter
paper and the excess of THF (approximately 25 mL)
was evaporated on a rotary evaporator. Compound VI
was crystallized by an addition of hexane and cooling
to 4◦C. The obtained white crystals were filtered and
dried under diminished pressure at ambient temper-
ature to afford 262 mg (0.7 mmol, 70 %) of VI. The
whole amount of the product was dissolved in MeOH
(25 mL), APTES (0.180 mL, 0.77 mmol, 1.1 eq.) was
added and the mixture was magnetically stirred at am-
bient temperature for 24 h. MeOH was evaporated on
a rotary evaporator, the oily residue was suspended in
0.1 M aqueous HCl (20 mL) and the aqueous layer was
extracted with ethyl acetate (EtOAc) (3 × 30 mL).
The combined organic layers containing product VII
were washed with distilled water (3 × 20 mL) until
neutral pH, dried with anhydrous MgSO4 and filtered.
The solvent was evaporated on a rotary evaporator
and the oily residue was dissolved in THF (10 mL) fol-
lowed by the addition of 1 M aqueous NaOH (2 mL).
The mixture was magnetically stirred at ambient tem-
perature for 1 h and THF was evaporated on a ro-
tary evaporator. Then, 1 M aqueous HCl (10 mL) was
added to the resulting aqueous layer and product I
was extracted with EtOAc (3 × 30 mL). The com-
bined organic layers were washed with distilled water
(3 × 20 mL) until neutral pH, dried with anhydrous
MgSO4 and filtered; the solvent was evaporated to af-
ford the crude product which was purified on a column
of silica gel using EtOAc/hexane (ϕr = 1 : 8) as the
eluent) to yield the desired product I (151 mg, 41 %)
as a white solid (m.p. 228–229◦C).
without additional catalysts
Compound
Solvent
T/◦C
Yield/%
I
MeOH
MeOH
Toluene/MeOH
Toluene/MeOH
25
60
25
60
17
30
27
79
II
MeOH
MeOH
Toluene/MeOH
Toluene/MeOH
25
60
25
60
19
33
30
83
(via COOH and B(OH)2 groups), susceptible to nucle-
ophilic attack of amines. Thus, it was decided to carry
out the synthesis in accordance with Fig. 3, starting
with 3-carboxyphenylboronic acid (3-CPBA) as the
initial substrate. The 3-CPBA molecule obtained from
the intermediary anhydride after the reaction with the
amine reacts with another 3-CPBA molecule to afford
the same anhydride and, via this repetition cycle, the
synthesis proceeds to completion. This method was
optimized and provided the best amidation results.
Since CPBA is poorly soluble in a number of or-
ganic solvents, apart from MeOH, the reactions were
carried out in MeOH and, for comparison, in toluene
with the addition of a small amount of MeOH to allow
dissolution of CPBA. The substrates were also found
to require higher temperatures (Table 1).
Product II (159 mg, 43 %) was obtained as a white
solid (m.p. 205–206◦C) in a similar manner under the
same conditions.
General method using N-hydroxysuccinimide
active esters (method A)
THF (20 mL) was added to a mixture of V (277 mg,
1 mmol) and HOSu (115 mg, 1 mmol). The solution
was cooled to 0◦C (ice bath) followed by the addition
of DCC (206 mg, 1 mmol) dissolved in THF (10 mL),
vigorous magnetic stirring for 1 h, and storage at 4◦C
for 12 h. The white precipitate of dicyclohexylurea was
General method using EDC as a coupling
reagent (method B)
A mixture of V (277 mg, 1 mmol) dissolved in
MeOH (5 mL) and EDC hydrochloride (192 mg,
1 mmol) dissolved in MeOH (15 mL) was magneti-
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J. Nowak-Jary/Chemical Papers 70 (5) 658–662 (2016)
Table 2. Spectral data of newly prepared compounds
661
Compound
Spectral data
I
FTIR (KBr), ν˜/cm−1: 3434 (NH, OH), 1544 (NH), 1637 (C O), 1019 (Si—O), 780 (Ph)
—
—
1H NMR (500 MHz, DMSO-d6), δ: 0.79 (m, 2H, SiCH2), 1.25 (t, 9H, 3 × CH3, J = 6.9 Hz), 1.96 (m, 2H, CH2),
2.56 (m, 2H, NCH2), 4.10 (q, 6H, 3 × OCH2, J = 7.1 Hz), 6.96 (t, 1H, H-Ph, J = 7.8 Hz), 7.24 (d, 1H, H-Ph, J =
7.8 Hz), 7.36 (d, 1H, H-Ph, J = 7.3 Hz), 7.31 (s, 1H, H-Ph), 7.96 (s, 2H, 2 × OH), 8.95 (s, 1H, NH)
13C NMR (100 MHz, DMSO-d6), δ: 8.23 (SiCH2), 19.48 (3 × CH3) 28.41 (CH2), 46.18 (NCH2), 56.3 (3 × OCH2),
—
128.49 (Ph), 130.51 (Ph), 131.20 (Ph), 131.57 (Ph), 135.85 (Ph), 139.14 (Ph), 168.38 (C O)
—
HRMS (ESI), m/z (Ir/%) (found/calc.): 370.237/369.234 ([M + H]+ , C16H28O6NSiB, 22.8)
FTIR (KBr), ν˜/cm−1: 3434 (NH, OH), 1544 (NH), 1640 (C O), 1062 (Si—O), 830 (Ph)
—
II
—
1H NMR (500 MHz, DMSO-d6), δ: 0.78 (m, 2H, SiCH2), 1.25 (t, 9H, 3 × CH3, J = 6.9 Hz), 1.96 (m, 2H, CH2),
2.61 (m, 2H, NCH2), 4.10 (q, 6H, 3 × OCH2, J = 7.2 Hz), 6.94 (d, 2H, H-Ph, J = 8.7 Hz), 7,18 (d, 2H, H-Ph, J =
8.9 Hz), 7.94 (s, 2H, 2 × OH), 9.00 (s, 1H, NH)
13C NMR (100 MHz, DMSO-d6), δ: 8.23 (SiCH2), 19.48 (3 × CH3) 28.41 (CH2), 46.18 (NCH2), 56.30 (3 × OCH2),
—
129.32 (1C, Ph), 130.10 (1C, Ph), 134.92 (2C, Ph), 138.53 (2C, Ph), 168.50 (C O)
—
HRMS (ESI), m/z (Ir/%) (found/calc.): 370.239/369.234 ([M + H]+ , C16H28O6NSiB, 26.4)
FTIR (KBr), ν˜/cm−1: 3430 (NH, OH), 1540 (NH), 1680 (C O) 780, 750 (Ph)
—
III
IV
—
1H NMR (500 MHz, DMSO-d6), δ: 7.05 (m, 1H, H-Ph), 7.21 (m, 2H, H-Ph), 7.40 (m, 2H, H-Ph), 7.62 (t, 1H, H-Ph,
J = 7.7 Hz), 7.67 (d, 1H, H-Ph, J = 1.37 Hz), 8.09 (d, 1H, H-Ph, J = 7.14 Hz), 8.15 (s, 2H, 2 × OH), 8.45 (s, 1H,
H-Ph), 10.28 (s, 1H, NH)
13C NMR (100 MHz, DMSO-d6), δ: 120.30 (2C, Ph), 123.54 (1C, Ph), 127.57 (1C, Ph), 128.28 (1C, Ph), 128.51
—
(2C, Ph), 131.66 (1C, Ph), 132.69 (1C, Ph), 134.94 (1C, Ph), 135.66 (1C, Ph), 139.11 (1C, Ph), 168.54 (C O)
—
HRMS (ESI), m/z (Ir/%) (found/calc.): 242.020/241.016 ([M + H]+ , C13H12O3NB, 35.2)
FTIR (KBr), ν˜/cm−1: 3430 (NH, OH), 1542 (NH), 1678 (C O) 830, 750 (Ph)
—
—
1H NMR (500 MHz, DMSO-d6), δ: 7.07 (m,1H, H-Ph), 7.25 (m, 2H, H-Ph), 7.42 (m, 2H, H-Ph), 7.93 (d, 2H, H-Ph,
J = 7.9 Hz), 8.00 (d, 2H, H-Ph, J = 8.2 Hz), 8.13 (s, 2H, 2 × OH), 9.83 (s, 1H, NH)
13C NMR (500 MHz, DMSO-d6), δ: 121.20 (2C, Ph), 124.96 (1C, Ph), 129.51 (2C, Ph), 130.28 (2C, Ph), 131.21
—
(2C, Ph), 134.72 (1C, Ph), 136.16 (1C, Ph), 139.11 (1C, Ph), 168.48 (C O)
—
HRMS (ESI), m/z (Ir/%) (found/calc.): 242.018/241.016 ([M + H]+ , C13H12O3NB, 37.6)
cally stirred at ambient temperature for 2 h to afford
VIII. Then, the same reaction steps and conditions as
described in method A were applied to afford VII and
finally I (89 mg, 24 %).
Product II was obtained as a white solid (96 mg,
26 %) in a similar manner under the same conditions.
ceed, confirming thus that the boronic acid group
(B(OH)2) plays the activating role.
Similarly, this optimized direct amidation method
was applied to the synthesis of compounds III and
IV using aniline as a nucleophile instead of APTES;
however, a small excess of CPBA (1.1 eq.) in rela-
tion to aniline was used to obtain better yields. Con-
sidering the significantly lower reactivity of aniline
compared to benzylamine and aliphatic amines (in-
cluding APTES), the resulting yields of 39 % and
42 % of products III (m.p. 245–246◦C) and IV (m.p.
222–223◦C), respectively, were considered satisfactory.
Spectral data of the new compounds I–IV are shown
in Table 2.
Optimized general method for direct amidation
of CPBA carbocyl group using APTES
˚
Toluene (25 mL) and activated 4 A molecular sieve
beads (0.5 g) were added to a solution of 3-CPBA
or 4-CPBA (166 mg, 1 mmol) in MeOH (3 mL) and
the mixture was magnetically stirred at 60◦C for 1 h.
APTES (0.468 mL, 2 mmol) was then added and the
mixture was stirred at 60◦C for additional 24 h fol-
lowed by the filtration through a pad of Celiteꢀ545
and evaporation of the solvent on a rotary evapora-
tor. The oily residue was suspended in 0.5 M aque-
ous HCl (20 mL) and the product was extracted
with EtOAc (3 × 30 mL). The combined organic lay-
ers were washed with distilled water (3 × 20 mL)
until neutral pH, dried with anhydrous MgSO4, fil-
tered and the solvent was evaporated to afford I
(292 mg, 79 %) or II (306 mg, 83 %) as white solid
Chemicals were of analytical grade and used as
received without further purification. All reagents
˚
and activated 4 A molecular sieve were purchased
from Sigma–Aldrich (Poland), and organic solvents
were purchased from Avantor Performance Materials
(Poland). TLC silica gel 60 plates and silica gel 60
(0.015–0.040 mm) for column chromatography were
obtained from Merck Millipore (Poland).
1H NMR and 13C NMR spectra were recorded in
DMSO-d6 on a Varian Unity 500 Plus spectrometer
(USA) using TMS as the internal standard. FTIR
spectra (KBr pellet technique) were measured on a
Nicolet iS50 FTIR spectrometer (USA) in the range
of 400–4000 cm−1. HRMS spectra (ESI-Q-TOF-MS)
were obtained on a Bruker micrOTOF-Q spectrometer
1
with purity higher than 95 % (according to H NMR
data).
Application of this optimized method to benzoic
acid revealed that the amidation reaction did not pro-
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J. Nowak-Jary/Chemical Papers 70 (5) 658–662 (2016)
(Germany). Melting points were recorded on a Kofler
hot block and are uncorrected.
Gu, L., Lim, J., Cheong, J. L., & Lee, S. S. (2014). MCF-
supported boronic acids as efficient catalysts for direct amide
condensation of carboxylic acids and amines. Chemical Com-
munications, 50, 7017–7019. DOI: 10.1039/c4cc01148a.
Jursic, B. S., & Zdravkovski, Z. (1993). A simple preparation
of amides from acids by heating of their mixture. Synthetic
Communications, 23, 2761–2770. DOI: 10.1080/0039791930
8013807.
Lanigan, R. M., Starkov, P., & Sheppard, T. D. (2013). Di-
rect synthesis of amides from carboxylic acids and amines
using B(OCH2CF3)3. The Journal of Organic Chemistry,
78, 4512–4523. DOI: 10.1021/jo400509n.
Lundberg, H., Tinnis, F., Selander, N., & Adolfsson, H. (2014).
Catalytic amide formation from non-activated carboxylic
acids and amines. Chemical Society Reviews, 43, 2714–2742.
DOI: 10.1039/c3cs60345h.
Montalbetti, C. A. G. N., & Falque, V. (2005). Amide bond for-
mation and peptide coupling. Tetrahedron, 61, 10827–10852.
DOI: 10.1016/j.tet.2005.08.031.
Mylavarapu, R. K., Kondaiah, G. C. M., Kolla, N., Veera-
malla, R., Koilkonda, P., Bhattacharya, A., & Bandichhor,
R. (2007). Boric acid catalyzed amidation in the synthesis of
active pharmaceutical ingredients. Organic Process Research
& Development, 11, 1065–1068. DOI: 10.1021/op700098w.
Noda, H., & Bode, J. W. (2014). Synthesis and chemoselec-
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lamines. Chemical Science, 5, 4328–4332. DOI: 10.1039/c4sc
00971a.
In conclusion, the new CPBA amides were ob-
tained by a very simple method without using any
coupling reagents or additional catalysts. So far, cat-
alytic potential of the amidation reaction of CPBA has
not been studied. Likewise, there are also no reports
regarding the direct amidation of the carboxyl group
of unprotected CPBA in a solution. It was demon-
strated in this study that CPBA is a suitable sub-
strate for the amidation reaction, and also an excellent
catalyst; the boronic part of one molecule activates
the carboxyl group of another molecule of the same
compound. Therefore, there is no need to use any ad-
ditional catalysts or coupling reagents. Because only
the substrates participate in the reaction, the forma-
tion of by-products is eliminated. The excess of amine
and a small amount of unreacted CPBA are removed
by simple extraction. The presented method can be
used as a general method for the synthesis of specific
CPBA amides.
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