Convenient synthesis of some 3-phenyl-1-benzofuran-2-carboxylic acid derivatives as new potential inhibitors of ClC-Kb channels

Article abstract of DOI:10.3987/COM-10-12070

Improved experimental conditions were carried out for the preparation in high yields of some 3-phenyl-1-benzofuran-2-carboxylic acids, potent inhibitors of ClC-K chloride channels. A one-pot condensation-cyclization was set up starting from different 2-hy

Full text of DOI:10.3987/COM-10-12070

HETEROCYCLES, Vol. 81, No. 12, 2010
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HETEROCYCLES, Vol. 81, No. 12, 2010, pp. 2865 - 2872. © The Japan Institute of Heterocyclic Chemistry
Received, 28th September, 2010, Accepted, 1st November, 2010, Published online, 9th November, 2010
DOI: 10.3987/COM-10-12070
CONVENIENT SYNTHESIS OF SOME 3-PHENYL-1-BENZOFURAN-2-
CARBOXYLIC ACID DERIVATIVES AS NEW POTENTIAL
INHIBITORS OF CLC-Kb CHANNELS
Luca Piemontese, Giuseppe Carbonara, Giuseppe Fracchiolla, Antonio
Laghezza, Paolo Tortorella, and Fulvio Loiodice*
Medicinal Chemistry Department, University of Bari “Aldo Moro”, via E.
Orabona, 4, 70126, Bari, Italy, e-mail: floiodice@farmchim.uniba.it
Abstract – Improved experimental conditions were carried out for the preparation
in high yields of some 3-phenyl-1-benzofuran-2-carboxylic acids, potent
inhibitors of ClC-K chloride channels. A one-pot condensation-cyclization was set
up starting from different 2-hydroxybenzophenones whose reactivity was
significantly affected from the electronic properties of their substituents.
ClC-Ka and ClC-Kb chloride channels are pivotal for renal salt reabsorption and water balance.1
Therefore, there is growing interest in identifying ligands that allow pharmacological interventions aimed
to modulate their activity. Recently, the 3-phenyl-1-benzofuran-2-carboxylic acids 1-6 (Figure 1) have
been reported as potent inhibitors of these channels proposing themselves as leads for the development of
agents capable of regulating diuresis.2
O
O
1. R1 = Cl
2. R1 = Cl
3. R1 = Br
4. R1 = Br
R2 = H
R2 = Cl
R2 = H
R2 = Cl
OH
R1
R2
5. R1 = Me R2 = H
1-6
6. R1 = H
R2 = H
O
O
7. R1 = Cl
8. R1 = Cl
9. R1 = Br
R2 = Me
R2 = H
R2 = Me
OH
R1
R2
7-9
Figure 1

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This promising activity prompted us to investigate the possibility to improve the synthesis of these
compounds which need to be available in great amount for in vivo studies. Differently from literature,3 in
fact, the procedure for the preparation of the ethyl ester of derivative 1, in our hands occurred in two steps
and very low yield. Herein we report improved experimental conditions for the preparation of ethyl
3-phenyl-1-benzofuran-2-carboxylates 1a-6a shown in Table 1. The cyclization reaction occurs in a
single step and with high yields providing, therefore, a simple and fast way to obtain the desired
compounds. Esters 7a-9a were also prepared to evaluate the importance of the benzene ring in position 3
of the benzofuran nucleus in affecting the reactivity of the reagents. Finally, the alkaline hydrolysis of all
the above esters allowed the achievement of the target 1-benzofuran-2-carboxylic acids 1-6 as well as 7-9.
The synthesis of ethyl 5-chloro-3-phenyl-1-benzofuran-2-carboxylate 1a was reported to occur by direct
condensation of 5-chloro-2-hydroxybenzophenone with ethyl 2-bromoacetate in dry toluene in the
presence of NaH. In our hands, instead, this reaction led to an intermediates mixture of ethyl
(2-benzoyl-4-chloro)phenoxyacetate
10
and
ethyl
5-chloro-3-hydroxy-3-phenyl-2,3-dihydro-1-benzofuran-2-carboxylate 11 with poor yield. The treatment
of this mixture with p-toluenesulfonic acid in boiling toluene afforded only small amounts of the ethyl
ester 1a after separation on silica gel column from the unreacted ester 10. Quantitative yields, however,
were obtained by using sodium ethoxide in refluxing absolute ethanol. The basic condition, in fact,
allowed, both the cyclization of 10 and the dehydration of 11 (Scheme 1).
O
O
OH
O
O
O
O
i
O
O
O
Br
+
+
OH
Cl
Cl
O
Cl
10
11
ii or iii
O
O
O
O
O
iv
OH
Cl
Cl
1
1a
Scheme 1. i) NaH (powder, 95%), dry toluene, reflux; ii) p-toluenesulfonic acid, toluene, reflux; iii)
EtONa, abs EtOH, 70 °C; iv) 2N NaOH, THF

HETEROCYCLES, Vol. 81, No. 12, 2010
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Searching in the literature for an alternative procedure allowing a direct and high yield synthesis of 1a,
we found that some furochromenes could be prepared by cyclization with diethyl bromomalonate in the
presence of K2CO3 in dry acetone.4 When we applied this procedure to the synthesis of 1a starting from
5-chloro-2-hydroxybenzophenone, the desired compound was obtained in one-pot reaction and in 99%
yield (Scheme 2).
OH
O
O
O
O
O
vi
R2
+
O
O
R1
R1
Br
R2
O
1a-9a
vii
O
O
OH
1-9
R1
R2
Scheme 2. vi) anhydrous K2CO3, acetone, reflux; vii) 2N NaOH, THF
The preparation of the other ethyl 3-phenyl-1-benzofuran-2-carboylates we were interested in, occurred
with similar results even though the reactivity of the starting ketone was influenced from the electronic
properties of its substituents.
Table 1
compound
1a
R1
Cl
R2
Yield
99%
2a
3a
Cl
99%
80%
Cl
Br
4a
5a
Br
98%
64%
Cl
Me

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HETEROCYCLES, Vol. 81, No. 12, 2010
72%
6a
H
7a
8a
9a
Cl
Cl
Br
Me
H
17%
20%
17%
Me
The presence, in fact, of an electron-withdrawing group in R1 increased the reactivity of the carbonylic
function. The chlorine atom turned out to be better than the bromine atom as shown from the 99% yield
for the preparation of 1a compared to 3a (80%). The presence of an additional chlorine atom on the
phenyl of R2 group showed a remarkable additive effect as demonstrated by the increased yield of 4a
(98%) compared to 3a. By contrast, as expected, the presence in R1 of an electron-donor group like a
methyl or the lacking of substituents decreased the electrophilic properties of ketone affording lower
yields for the corresponding benzofurans 5a and 6a. The influence on the reactivity of the carbonylic
group by the R2 group was even greater. Starting, in fact, from acetophenone (R2 = methyl) or
benzaldehyde (R2 = H), the corresponding benzofurans 7a-9a were obtained in low yields (17-20%).
Finally, all the above esters were easily hydrolyzed to the target acids by treatment with a 2N NaOH/THF
mixture.5 Yields as high as 77-94% were obtained with the exception of acid 7 (52%).
In conclusion, a simple, fast and high yield synthesis of the 3-phenyl-1-benzofuran-2-carboxylic acids 1-6
was carried out by significantly modifying a previously reported procedure. The reactivity of the starting
benzophenone was significantly affected by the electronic properties of its substituents with
electron-withdrawing groups affording the best yields. The reactivity of the starting carbonylic compound
was even more greatly reduced by substitution of benzophenone with acetophenone or benzaldehyde.
Importantly, this improved procedure for the preparation of acids 1-6 allows the availability of gram scale
of these potent ClC-K chloride channel inhibitors for in vivo studies.
EXPERIMENTAL
General. All commercial reagents and solvents were used without further purification. Reactions were
monitored by TLC analysis using silica-coated TLC plates (Merck F 60254) and visualized under UV
light. Column chromatography was performed on ICN silica gel 60 J (63–200 mm) as a stationary phase.
Melting points were determined in open capillaries on a Gallenkamp electrothermal apparatus and are
uncorrected. Mass spectra were recorded with an HP GC–MS 6890–5973 MSD spectrometer, electron
impact 70 eV, equipped with HP chemstation. 1H-NMR spectra were recorded in CDCl3 or DMSO-d6 on
a Varian-Mercury 300 (300 MHz) spectrometer at room temperature (20 °C). Chemical shifts are
expressed as parts per million (δ).

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Ethyl (2-benzoyl-4-chloro)phenoxyacetate and ethyl 5-chloro-3-hydroxy-3-phenyl-2,3-dihydro-
1-benzofuran-2-carboxylate. (Scheme 1, step i) NaH powder (95%, 190 mg, 7.9 mmol) was carefully
added, under nitrogen atmosphere, to a solution of 5-chloro-2-hydroxybenzophenone (1.5 g, 5.3
mmol) in 20 mL of anhydrous toluene. The resulting mixture was stirred and was refluxed for 15 minutes.
Then a solution of ethyl 2-bromoacetate (1.5 g, 9.0 mmol) in 10 mL of anhydrous toluene was slowly
dropped and the mixture was refluxed 11 h. After cooling at room temperature it was treated with water.
The organic solution was separated and evaporated and the residue oil was taken up with Et2O; the
organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced
pressure to afford the crude product, which was purified by column chromatography on silica gel using
petroleum ether-EtOAc as eluent (95:5) to give the mixture (94.5:5.5, as determined by GC-MS and
1H-NMR) as a white solid (890 mg).
Ethyl (2-benzoyl-4-chloro)phenoxyacetate (10). 1H-NMR (300 MHz, CDCl3): 1.21 (t, 3H, CH3; J = 7.2
Hz), 4.16 (q, 2H, CH3-CH2-O; J = 7.2 Hz), 4.51 (s, 2H, O-CH2-CO), 6.77-6.82, 7.36-7.60 and 7.83-7.87
(m, 8H, aromatics); GC-MS (tR: 13.22 min): m/z 320 (M+ +2) (9), 318 (M+) (27), 244 (M+ – C3H6O2)
+
+
(100), 105 (M+ – C9H6ClO4 ) (66), 91 (M+ - C10H8ClO4 ) (98).
Ethyl 5-chloro-3-hydroxy-3-phenyl-2,3-dihydro-1-benzofuran-2-carboxylate (11). 1H-NMR (300
MHz, CDCl3): 1.23 (t, 3H, CH3; J = 7.2 Hz), 2.03 (s, 1H, OH), 4.17 (q, 2H, CH3-CH2-O; J = 7.2 Hz), 5.16
(s, 1H, CH), 6.52-6.58 and 6.95-7.09 (m, 8H, aromatics); GC-MS (tR: 12.91 min): m/z 320 (M+ +2) (17),
318 (M+) (42), 244 (M+ – C3H6O2) (100).
Ethyl 5-chloro-3-phenyl-1-benzofuran-2-carboxylate (Scheme 1, step ii).
p-Toluenesulfonic acid (1 g, 5.7 mmol) was added to a solution in toluene (30 mL) of the mixture
obtained in step (i). The mixture was refluxed for 13 h. Then the solvent was distilled off and the oily
residue was dissolved in Et2O; the organic phase was washed with brine and dried over Na2SO4. The
solvent was removed under reduced pressure to give the crude oil, which was purified by column
chromatography on silica gel using petroleum ether/EtOAc as eluent (95:5) to give the desired product as
a white solid (60 mg).
Ethyl 5-chloro-3-phenyl-1-benzofuran-2-carboxylate (Scheme 1, step iii).
A solution of the mixture obtained in step (i) (200 mg) in absolute EtOH (2mL) was dropped to a solution
of sodium ethoxide (0.55 mmol) in absolute EtOH (5 mL). After reflux for 1 h, the mixture was cooled at
room temperature. The solvent was removed under reduced pressure to afford the desired product in
quantitative yield.
General procedure for the synthesis of ethyl 1-benzofuran-2-carboxylate derivates 1a-9a (Scheme 2,
step vi).
To a suspension of 16.2 g of anhydrous K2CO3 (0.012 mol) in 195 mL of acetone was added, under

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nitrogen atmosphere, the suitable ketone or aldehyde (0.012 mol). The mixture was stirred 30 min and
then a solution of diethyl bromomalonate (2.8 g, 0.012 mol) in acetone (35 mL) was slowly dropped. The
mixture was refluxed 16-18 h. The solvent was evaporated in vacuo and the residue was poured into Et2O
and water, washed with 0.5 N NaOH and water, dried with Na2SO4 and filtered. The organic solution was
evaporated to give a crude solid, which was purified by column chromatography on silica gel using
petroleum ether/EtOAc as eluent (9:1) to afford the desired products in different yields.
Ethyl 5-chloro-3-phenyl-1-benzofuran-2-carboxylate (1a). Yield: 99%; mp 105-106 °C; 1H-NMR (300
MHz, DMSO-d6) δ (ppm): 1.27 (t, 3H, CH3; J = 7.2 Hz), 4.35 (q, 2H, CH2; J = 7.2 Hz), 7.41–7.58 (m, 8H,
aromatics); GC-MS: m/z ( 302, M+ + 2) (35), 300 (M+) (100). Anal. Calcd for C17H13ClO3: C, 67.89; H,
4.36. Found: C, 68.12; H, 4.31.
Ethyl 5-chloro-3-(2-chlorophenyl)-1-benzofuran-2-carboxylate (2a). Yield: 99%; mp 60-63 °C;
1H-NMR (300 MHz, CDCl3) δ (ppm): 1.18 (t, 3H, CH3; J = 7.2 Hz), 4.17-4.36 (m, 2H, CH2; J = 7.2 Hz),
7.32-8.32 (m, 7H, aromatics); GC-MS: m/z 338 (M+ + 4) (1), 336 (M+ + 2) (2), 334 (M+) (3), 271 (M+-
+
C3H5O2 ) (100). Anal. Calcd for C17H12Cl2O3: C, 60.92; H, 3.61. Found: C, 60.70; H, 3.70.
Ethyl 5-bromo-3-phenyl-1-benzofuran-2-carboxylate (3a). Yield: 80%; mp 128-130 °C; 1H-NMR (300
MHz, CDCl3) δ (ppm): 1.27 (t, 3H, CH3; J = 7.2 Hz), 4.33 (q, 2H, CH2; J = 7.2 Hz), 7.25-7.71 (m, 8H,
aromatics); GC-MS: m/z 346 (M++ 2) (97), 344 (M+) (100). Anal. Calcd for C17H13BrO3: C, 59.15; H,
3.80. Found: C, 58.86; H, 3.97.
Ethyl 5-bromo-3-(2-chlorophenyl)-1-benzofuran-2-carboxylate (4a). Yield: 98%; mp 82-84 °C;
1H-NMR (300 MHz, CDCl3) δ (ppm): 1.18 (t, 3H, CH3; J = 7.2 Hz), 4.28 (q, 2H, CH2; J = 7.2 Hz),
7.26-7.59 (m, 7H, aromatics); GC-MS: m/z 382 (M++ 4) (3), 380 (M++ 2) (4), 378 (M+) (1), 343 (M+- Cl)
(60), 315 (M+ – COCl) (100). Anal. Calcd for C17H12BrClO3: C, 53.78; H 3.19; Found: C, 53.88; H, 3.16.
Ethyl 5-methyl-3-phenyl-1-benzofuran-2-carboxylate (5a). Yield: 64%; mp 80-82 °C; 1H-NMR (300
MHz, CDCl3) δ (ppm): 1.28 (t, 3H, CH3-CH2; J = 7.3 Hz), 2.43 (s, 3H, CH3-Ph), 4.33 (q, 2H, CH2; J = 7.3
Hz), 7.25-7.59 (m, 8H, aromatics); GC-MS: m/z 280 (M+) (100), 208 (M+ – C3H4O2) (64). Anal. Calcd for
C18H16O3: C, 77.12; H 5.75. Found: C, 77.22; H, 5.71.
1
Ethyl 3-phenyl-1-benzofuran-2-carboxylate (6a). Yield: 72%; mp 63-65 °C; H-NMR (300 MHz,
CDCl3) δ (ppm): 1.29 (t, 3H, CH3; J = 7.2 Hz), 4.35 (q, 2H, CH2; J = 7.2 Hz), 7.25-7.65 (m, 9H,
aromatics); GC-MS: m/z 266 (M+) (100), 194 (M+ - C3H4O2) (62). Anal. Calcd for C17H14O3: C, 76.68; H,
5.30. Found: C, 76.91; H, 5.22.
1
Ethyl 5-chloro-3-methyl-1-benzofuran-2-carboxylate (7a). Yield: 17%; mp 65-67 °C; H-NMR (300
MHz, DMSO-d6) δ (ppm): 1.44 (t, 3H, CH3CH2; J = 7.2 Hz), 2.55 (s, 3H, CH3), 4.45 (q, 2H, CH2; J = 7.2
Hz), 7.37 (m, 2H, aromatics), 7.60 (m, 1H, aromatic); GC-MS: m/z 240 (M+ +2) (37), 238 (M+) (100).
Anal. Calcd for C12H11ClO3: C, 60.39; H, 4.65. Found: C, 60.44; H, 4.55.

HETEROCYCLES, Vol. 81, No. 12, 2010
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1
Ethyl 5-chloro-1-benzofuran-2-carboxylate (8a). Yield: 20%; mp 56-58 °C; H-NMR (300 MHz,
CDCl3) δ (ppm): 1.43 (t, 3H, CH3; J = 7.2 Hz), 4.44 (q, 2H, CH2; J = 7.2 Hz), 7.38-7.66 (m, 4H,
aromatics); GC-MS: m/z 226 (M+ +2) (30), 224 (M+) (85), 198 ((M+ +2) – C2H4) (36), 196 (M+ – C2H4)
(100),181 (M+ + 2– C2H5O) (37), 179 (M+ – C2H5O) (99). Anal. Calcd for C11H9ClO3: C, 58.81; H, 4.04.
Found: C, 58.88; H 3.93.
1
Ethyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (9a). Yield: 17%; mp 90-92 °C; H-NMR (300
MHz, CDCl3) δ (ppm): 1.44 (t, 3H, CH3-CH2; J = 7.2 Hz), 2.55 (s, 3H, CH3), 4.45 (q, 2H, CH2; J = 7.2
Hz), 7.26-7.83 (m, 3H, aromatics); GC-MS: m/z 284 (M+ + 2) (98), 282 (M+) (100), 256 ((M++ 2) -
C2H4) (70), 254 (M+ - C2H4) (73), 239((M++ 2) - OC2H4) (45), 237 (M+ - OC2H4) (45). Anal. Calcd for
C12H11BrO3: C, 50.91; H 3.91. Found: C, 50.73; H, 3.96.
General procedure for the synthesis of acids 1-9. (Scheme 1, step iv and Scheme 2, step vii) The
ethyl 1-benzofuran-2-carboxylate(10 mmol), obtained from the reaction described above, was stirred at
room temperature with 2N NaOH (175 mL) in THF (175 mL) for 4–6 h. The organic solvent was distilled
off under reduced pressure and the aqueous phase was washed with Et2O, acidified to pH 1 with 6N
HCl, and extracted with Et2O (3x35 mL). The combined organic extracts were dried over Na2SO4, and the
solvent was removed under reduced pressure to afford the desired acids as solids, which were purified by
crystallization from CHCl3/n-hexane.
1
5-Chloro-3-phenyl-1-benzofuran-2-carboxylic acid (1). Yield: 77%; mp 254-255 °C; H-NMR (300
MHz, DMSO-d6) δ (ppm): 7.41–7.82 (m, 8H, aromatics), 13.62 (bs, 1H, COOH, D2O exchangeable);
GC-MS: m/z (methyl ester) 288 (M+ + 2) (35), 286 (M+) (100). Anal. Calcd for C15H9ClO3: C, 66.07; H,
3.33. Found: C, 66.31; H, 3.30.
5-Chloro-3-(2-chlorophenyl)-1-benzofuran-2-carboxylic acid (2). Yield: 88%; mp 215-218 °C;
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 7.36-7.65 (m, 6H, aromatics), 13.57 (bs, COOH, D2O
exchangeable); GC-MS: m/z (methyl ester) 324 (M+ +4) (0.1) , 322 (M+ +2) (1), 320 (M+) (3), 285 ((M+
+2)– Cl) (35), 285 (M+ – Cl) (100). Anal. Calcd for C15H8Cl2O3: C, 58.66; H, 2.63. Found: C, 58.20; H,
2.73.
1
5-Bromo-3-phenyl-1-benzofuran-2-carboxylic acid (3). Yield: 85%; mp 248-251 °C; H-NMR (300
MHz, DMSO-d6) δ (ppm): 7.42-7.76 (m, 7H, aromatics), 13.51 (bs, COOH, D2O exchangeable);
GC-MS: m/z (methyl ester) 332 (M+ +2) (98), 330 (M+) (100), 299 (M+ – CH3O) (50), 301 ((M++2)
–CH3O) (49). Anal. Calcd for C15H9BrO3: C, 56.81; H, 2.86. Found: C, 56.92; H, 3.03.
5-Bromo-3-(2-chlorophenyl)-1-benzofuran-2-carboxylic acid (4). Yield: 89%; mp 218-219 °C;
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 7.36-7.62 (m, 6H, aromatics), 13.46 (bs, COOH, D2O
exchangeable); GC-MS: m/z (methyl ester) 366 (M++ 2) (26), 364 (M+) (27), 335 ((M+ + 2) – CH3O) (98),
333 (M+ – CH3O) (100). Anal. Calcd for C15H8BrClO3: C, 51.24; H 2.29; Found: C, 51.20; H, 2.34.

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HETEROCYCLES, Vol. 81, No. 12, 2010
1
5-Methyl-3-phenyl-1-benzofuran-2-carboxylic acid (5). Yield: 94%; mp 233-234 °C; H-NMR (300
MHz, DMSO-d6) δ (ppm): 2.38 (s, 3H, CH3-Ph), 7.31- 7.62 (m, 8H, aromatics), 13.23 (bs, 1H, COOH,
D2O exchangeable); GC-MS: m/z (methyl ester) 266 (M+) (100), 235 (M+ - CH3O) (53). Anal. Calcd
for C16H12O3: C, 76.18; H 4.79. Found: C, 76.12; H, 4.74.
1
3-Phenyl-1-benzofuran-2-carboxylic acid (6). Yield: 93%; mp 236-238 °C; H-NMR (300 MHz,
DMSO-d6) δ (ppm): 7.32- 7.75 (m, 8H, aromatics), 13.42 (bs, COOH, D2O exchangeable);GC-MS: m/z
(methyl ester) 252 (M+) (100), 221 (M+ – CH3O) (52). Anal. Calcd for C15H10O3: C, 75.62; H, 4.23.
Found: C, 75.96; H, 4.22.
1
5-Chloro-3-methyl-1-benzofuran-2-carboxylic acid (7). Yield: 52%; mp 268-269 °C; H-NMR (300
MHz , DMSO-d6) δ (ppm): 3.50 (s, 3H, CH3), 7.50 (m, 1H, aromatic), 7.70 (m, 1H, aromatic), 7.90 (m,
1H, aromatic), 13.50 (bs, COOH, D2O exchangeable); GC-MS: m/z (methyl ester) 226 (M+ +2) (28), 224
(M+) (100), 193 (M+ – CH3O) (87). Anal. Calcd for C10H7ClO3: C, 57.03; H, 3.35. Found: C, 57.34; H,
3.53.
1
5-Chloro-1-benzofuran-2-carboxylic acid (8). Yield: 94%; mp 215-217 °C; H-NMR (300 MHz,
DMSO-d6) δ (ppm): 7.30- 7.51 (m, 4H, aromatics), 13.66 (bs, COOH, D2O exchangeable); GC- MS: m/z
(methyl ester) 212 (M++2) (34), 210 (M+) (88), 181 ((M++2) – CH3O) (42), 179 (M+ - CH3O) (100). Anal.
Calcd for C9H5ClO3: C, 54.99; H, 2.56. Found: C, 54.87; H 2.73.
1
5-Bromo-3-methyl-1-benzofuran-2-carboxylic acid (9). Yield: 77%; mp 263-264 °C; H-NMR (300
MHz, DMSO-d6) δ (ppm): 2.49 (s, 3H, CH3), 7.61 (m, 2H, aromatics), 8.01 (m, 1H, aromatic), 13.52 (bs,
COOH, D2O exchangeable); GC-MS: m/z (methyl ester) 270 (M++2) (97), 268 (M+) (100), 239 ((M++2) –
CH3O) (59), 237 (M+ - CH3O) (56). Anal. Calcd for C10H7BrO3: C, 47.09; H 2.77. Found: C, 46.93; H,
2.86.
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