Palladium-catalyzed external-CO-free carbonylation of aryl bromides using 2,4,6-trichlorophenyl formate

Article abstract of DOI:10.1248/cpb.c18-00042

A practical Pd-catalyzed carbonylation of (hetero)aryl bromides using a crystalline carbon monoxide (CO) surrogate, 2,4,6-trichlorophenyl formate (TCPF), was developed. This reaction proceeds without the slow addition technique that was previously required and with a low catalyst loading (1mol%). The utility of this Pd-catalyzed external-CO-free carbonylation using TCPF was demonstrated in the synthesis of a histone deacetylase inhibitor.

Full text of DOI:10.1248/cpb.c18-00042

Chemical and Pharmaceutical Bulletin Advance Publication by J-STAGE
DOI:10.1248/cpb.c18-00042
Advance Publication
February 14, 2018
Chem. Pharm. Bull.
Regular Article
Palladium-Catalyzed External-CO-Free Carbonylation of Aryl Bromides
Using 2,4,6-Trichlorophenyl Formate
Hideyuki Konishi, Tomoyuki Sekino, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka
422-8526, Japan.
* Correspondence e-mail: manabe@u-shizuoka-ken.ac.jp
Ⓒ 2018 The Pharmaceutical Society of Japan

Summary
A practical Pd-catalyzed carbonylation of (hetero)aryl bromides using a crystalline carbon
monoxide (CO) surrogate, 2,4,6-trichlorophenyl formate (TCPF), was developed. This
reaction proceeds without the slow addition technique that was previously required and with
a low catalyst loading (1 mol%). The utility of this Pd-catalyzed external-CO-free
carbonylation using TCPF was demonstrated in the synthesis of a histone deacetylase
inhibitor.
Keywords
Carbonylation; 2,4,6-Trichlorophenyl formate; Aryl bromide; Carbon monoxide surrogate
Chemical and Pharmaceutical Bulletin Advance Publication

Aromatic carboxylic acid derivatives are important compounds that comprise many drugs,
fine chemicals, and their synthetic intermediates. Aromatic halides constitute useful starting
materials in the synthesis of aromatic carboxylic acid derivatives. There are mainly two
synthetic approaches that can be used to obtain the carboxylic acid derivatives from aromatic
halides: metal‒halogen exchange using metals or organometallic reagents followed by
treatment with carbon dioxide1‒3) and derivatization of the resulting carboxylic acids, and
Pd-catalyzed carbonylation in the presence of nucleophiles.4‒7) The former method involves
a strongly basic metalated intermediate that is incompatible with sensitive functional groups,
while the latter proceeds smoothly under weakly basic conditions.
Because of the versatility of Pd-catalyzed carbonylation, it has been widely studied since
the pioneering work of Heck et al. reported in 1974.8‒10) However, because the reaction uses
toxic and flammable carbon monoxide (CO) gas, special cautions are required, especially
when the reaction is conducted on a laboratory scale. To solve this problem, many research
groups have worked on the development of CO surrogates that generate CO in situ, and
several safe and facile carbonylation reactions using CO surrogates have been reported.11‒18)
Recently, we and Tsuji et al. independently reported Pd-catalyzed carbonylation reactions
using a liquid CO surrogate, phenyl formate. It was found to react with weak bases (e.g.,
NEt3) at elevated temperatures to form CO and phenol, and could be employed in
external-CO-free carbonylation reactions in situ.19‒21) In the course of our investigations on
more reactive CO surrogates, we also developed a highly reactive crystalline CO surrogate,
2,4,6-trichlorophenyl formate (1, TCPF).22) While it is highly air-stable and can be stored
under ambient conditions, the generation of CO from 1 occurs rapidly (in ca. 30 min) in the
presence of NEt3, even at room temperature (rt). The utilization of 1 enabled us to conduct
the Pd-catalyzed aryloxycarbonylation of iodoarenes and alkenyl triflates at rt. We also
reported facile, scalable procedures to prepare TCPF from low-priced starting materials and
their applications in gram-scale Pd-catalyzed carbonylation reactions.23) Furthermore, the
resulting aryloxycarbonylated products, trichlorophenyl esters, are electrophilic enough to
be easily transformed with various nucleophiles to give other derivatives such as amides and
thioesters in high yields.24,25) Therefore, carbonylation using 1 and subsequent
transformations can be useful for synthesizing various carboxylic acid derivatives.22,26‒28)
Despite the advantages of 1, the carbonylation of bromoarenes, which are considerably
Chemical and Pharmaceutical Bulletin Advance Publication

cheaper than iodoarenes and are readily available, requires high temperatures (100 °C) and
the slow addition of a solution of 1 (over 3 h) to the reaction mixture (Chart 1a).22) This
procedure is not practical, since a syringe pump is required for the slow addition. Herein, we
present a practical Pd-catalyzed external-CO-free carbonylation of bromoarenes using TCPF,
without the use of a syringe pump (Chart 1b). In addition, this improved procedure can also
be conducted with a smaller amount of the Pd catalyst.
Chart 1. Pd-Catalyzed Carbonylation of Bromoarenes Using TCPF (1)
Results and Discussion
To identify the optimal conditions for the carbonylation of bromoarenes using TCPF
without the use of a syringe pump, we examined the effects of various bases on the
carbonylation of 4-bromotoluene (2a) using 2.0 equiv of 1 and a catalytic amount of
Pd(OAc)2 and Xantphos in toluene at 80 °C (Table 1). The reactions were conducted in a test
tube, and all materials were added before the tube was sealed with a screw cap and heated in
an oil bath. Organic (entries 1‒7) and inorganic bases (entries 9‒16) were screened. NEt3 or
NBu3, which were used in the previous work,22) resulted in relatively good yields, albeit not
very high (entries 4 and 5). Interestingly, sterically bulky iPr2NEt was totally ineffective
(entry 6). Among all the tested bases, DBU proved to be optimal (entry 7), affording 3a in a
high yield. Furthermore, with DBU as a base, the carbonylated product was obtained in 78%
Chemical and Pharmaceutical Bulletin Advance Publication

yield with 1 mol% of Pd(OAc)2 (entry 8).
Table 1. Effect of Bases on Carbonylation of Bromoarenes Using 1
entry
1
base
yield (%)
trace
6
NaOAc
pyridine
DABCO
NEt3
2
3
26
4
79
5
NBu3
83
6
iPr2NEt
DBU
trace
93
7
8a
DBU
78
9
K2HPO4
K3PO4
NaHCO3
Na2CO3
Li2CO3
K2CO3
Rb2CO3
Cs2CO3
trace
19
10
11
12
13
14
15
16
13
58
trace
trace
48
79
a) Pd(OAc)2 (1 mol%) and Xantphos (2 mol%) were used.
Next, we tested various solvents in the carbonylation reaction using 1.5 equiv of 1 in the
presence of 1 mol% of Pd(OAc)2, 2 mol% of Xantphos, and 2.0 equiv of DBU (Table 2,
Chemical and Pharmaceutical Bulletin Advance Publication

entries 1‒8). Less polar solvents appeared to be better suited for this reaction than polar
solvents, and toluene was determined to be the optimal solvent. We observed too fast
generation of CO during the addition of DBU when polar solvents were used, which might
cause a CO leak though the hole made on a septum by piercing the syringe. We also
examined the effect of the amount of 1 (entries 8‒10), because 1 generates CO rapidly in the
reaction with DBU in toluene at 80 °C, therefore the amount of 1 affects the CO pressure
inside the sealed reaction vessel. Since high CO pressure often retards the oxidative addition
of bromoarenes to the Pd center due to the π-acidity of CO,29,30) the internal CO pressure
would affect the Pd-catalyzed process. Two equiv of 1 were optimal for the reaction (entry 9),
and 1.5 or 3.0 equiv of 1 gave slightly lower yields of the desired ester (entries 8 and 10).
These results suggest that appropriate CO pressure is important for the reaction to proceed
smoothly. Pd sources were also screened, and Pd(PhCN)2Cl2 was found to be a more
effective catalyst than Pd(OAc)2, affording the desired product in >99% yield (entry 11).
Chemical and Pharmaceutical Bulletin Advance Publication

Table 2. Optimization of Reaction Conditions
entry
solvent
CH3CN
DMF
X (equiv)
1.5
yield (%)
62
1
2
1.5
43
3
NMP
1.5
13
4
DCE
1.5
35
5
PhCF3
THF
1.5
67
6
1.5
62
7
DME
1.5
trace
72
8
toluene
toluene
toluene
toluene
1.5
9
2.0
78
10
11a)
3.0
65
2.0
>99
a) Pd(PhCN)2Cl2 was used instead of Pd(OAc)2.
With the optimal reaction conditions in hand, we examined the substrate scope of the
reaction (Table 3). The reaction proceeded in 75–91% yields (3a–g) with substrates bearing a
variety of para-substituents such as methoxy, chloro, ethoxycarbonyl, formyl, and cyano
groups. In contrast, the substrate bearing a nitro group resulted in a modest yield of 3h (34%).
Meta-substituted substrates bearing methyl and methoxy groups reacted with 2 to provide 3i
and 3j in 83–91% yield. On the other hand, the carbonylation of ortho-substituted
bromoarenes with methyl and chloro groups was sluggish, yielding the product in 24–52%
yields (3k, l), probably due to the steric effects of the substituents. However, to our delight,
carbonylation of the ortho cyano substrate gave the product in 84% yield (3m). While
Chemical and Pharmaceutical Bulletin Advance Publication

1-bromonaphthalene gave the product in 59% yield (3n), the reaction of
2-bromonaphthalene gave the product in >99% yield (3o). Furthermore, the reactions of
electron-deficient bromoheteroarenes, 3-bromopyridine and 5-bromopyrimidine, proceeded
smoothly to give the product in 89% (3p) and 67% yields (3q), respectively. Electron-rich
bromoheteroarenes such as 3- and 2-bromothiophene reacted with 1 to afford the
corresponding esters in 88–89% yields (3r, s). The carbonylation reaction of phenyl triflate
afforded the desired product in 79% yield. In addition, the carbonylation reaction was
applied to the gram-scale synthesis of 3a, and 1.04 g (66% yield) of the desired product was
obtained in a single run. The reaction with 0.5 mol% of the Pd catalyst gave 3a in 79% yield
in 48 h.
Chemical and Pharmaceutical Bulletin Advance Publication

Table 3. Substrate Scope of Carbonylation Using 1
Cl
Cl
O
Pd(PhCN)2Cl2 (1 mol%)
Xantphos (2 mol%)
DBU (2.0 equiv)
O
H
O
Cl
OAr
1
(2 equiv)
+
Me
toluene
80 °C, 24 h
Ar = 2,4,6-Cl3C6H2
R
Br
3a–s
CO2Ar
R1
CO2Ar
CO2Ar
R1
R1
R1 = Me
Me
3a (>99%)
3a (66%)a)
3a (79%)b)
3b (90%)
3c (75%)
3d (88%)
R1 = Me 3i
OMe 3j
(83%)
(91%)
R1 = Me
(24%)
3k
Cl 3l (52%)
CN 3m (84%)
Me
H
OMe
Cl
R1
R2
CO2Et 3e (93%)
CHO
CN
NO2
3f (85%)
3g (91%)
3h (34%)
R1 = CO2Ar, R2 = H 3n (59%)
R1 = H, R2 = CO2Ar
(>99%)
3o
R1
CO2Ar
CO2Ar
Y
R2
S
N
R1 = CO2Ar, R2 = H
R1 = H, R2 = CO2Ar
3b
(79%)
Y = CH 3p
3q
(89%)
(67%)
3r
3s
(89%)
(88%)
(from PhOTf)
N
a) 5.0 mmol scale. 1.04 g of the product was obtained. b) Pd(PhCN)2Cl2 (0.5 mol%) and
Xantphos (1 mol%) were used. The reaction was performed for 48 h.
Finally, to demonstrate the utility of the reaction, we applied it to the synthesis of a histone
deacetylase (HDAC) inhibitor (7) developed by Nielsen et al. (Chart 2) via solid-phase
synthesis.31)
Bromothiophene
4,
which
was
prepared
from
(5-bromothiophen-2-yl)methanamine32) and 4-fluorobenzoyl chloride, smoothly reacted
with 1 to afford trichlorophenyl ester 5 in 93% yield on a gram scale. Ester 5 was then
condensed with (S)-O-benzyl-α-alaninehydroxamic acid TFA salt to give amide 6.
Deprotection of the benzyl group with BCl3 gave 7. Thus, the carbonylation reaction using
Chemical and Pharmaceutical Bulletin Advance Publication

TCPF enabled the efficient solution-phase synthesis of HDAC inhibitor 7.
Chart 2. Synthesis of HDAC inhibitor 7. Reagents and conditions: (i) 4 (1.00 g, 3.18 mmol),
1 (2.0 equiv), DBU (2.0 equiv), Pd(PhCN)2Cl2 (1 mol%), Xantphos (2 mol%), toluene, 80 °C,
24 h, 93% (1.35 g of 5 was obtained.); (ii) (S)-O-benzyl-α-alaninehydroxamic acid TFA salt,
NEt3, DMAP (5 mol%), THF, 55 °C, 44 h, 92%; (iii) BCl3, CH2Cl2, 0 °C, 1 h, 49%.
Conclusion
In summary, we developed the Pd-catalyzed carbonylation of bromoarenes and an aryl
triflate using TCPF, an easily accessible crystal CO surrogate, without the previously
required slow addition technique. Moreover, the reaction could be conducted with a low
catalyst loading (1 mol%) on a gram scale. The developed carbonylation reaction does not
require a syringe pump, and can be conducted in a simple test tube or flask. Therefore, this
method provides a practical, safe, and easy route for the transformation of bromoarenes into
trichlorophenyl esters with a wide viable substrate scope including heteroarenes.
Chemical and Pharmaceutical Bulletin Advance Publication

Furthermore, the synthesis of an HDAC inhibitor was realized in only a few short steps from
a bromothiophene derivative, highlighting the potential utility of this reaction. Further
investigations on other carbonylative reactions using this CO surrogate are underway and
will be reported in due course.
Experimental
General Experimental Methods All reactions were performed in oven-dried or
flame-dried glassware under an argon atmosphere. Reactions were monitored by TLC on
Merck silica gel 60 F254 plates visualized with a UV lamp at 254 nm. Column
chromatography was performed on Merck silica gel 60, and preparative TLC was
performed on Merck silica gel 60 F254 0.5 mm plates. NMR spectra were measured on a
1
13
JEOL AL-400 NMR spectrometer (400 MHz for H spectra and 100 MHz for C spectra)
1
13
or a JEOL ECX-500 NMR spectrometer (500 MHz for H spectra and 125 MHz for C
spectra) and are quoted in ppm for measurement against a tetramethylsilane (TMS) or
residual solvent peak as an internal standard. Infrared spectra were measured on a
SHIMADZU IR Prestige-21 spectrometer (ATR). High-resolution mass spectra (HRMS)
were measured on a Bruker MicrOTOF time-of-flight mass spectrometer (ESI) and a JEOL
JMS-T100TD time-of-flight mass spectrometer (DART). Melting points were measured
using a YAZAWA MICRO MELTING POINT BY-1.
General experimental procedure for carbonylation of bromoarenes using
2,4,6-trichlorophenyl formate (1)
Pd(PhCN)2Cl2 (1.9 mg, 5.00 µmol, 1 mol%), Xantphos (1.9 mg, 10.0 µmol, 2 mol%),
bromoarene (0.500 mmol), 123) (226 mg, 1.00 mmol, 2.0 equiv), and toluene (1.0 mL) were
added to a 10 mL test tube with a septum containing a magnetic stirring bar. The tube was
evacuated and backfilled with Ar three times. DBU (150 μL, 1.00 mmol, 2.0 equiv) was
added to the mixture using a syringe through the septum. The tube was screw-capped and
warmed to 80 °C in an oil bath. The mixture was stirred for 24 h. After cooling to rt, the
mixture was quenched with aq. citric acid (10% w/v), diluted with CH2Cl2 and H2O,
extracted with CH2Cl2 from aqueous layer, washed with H2O, aq. Na2CO3 (0.5 M), and
brine, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by
preparative TLC (SiO2, hexane/EtOAc 30/1) to afford the desired ester.
Chemical and Pharmaceutical Bulletin Advance Publication

2,4,6-Trichlorophenyl 4-methylbenzoate (3a)22)
White solid; 158 mg, >99% yield.
2,4,6-Trichlorophenyl benzoate (3b)22)
White solid; 135 mg, 90% yield.
2,4,6-Trichlorophenyl 4-methoxybenzoate (3c)22)
White solid, 125 mg, 75% yield.
2,4,6-Trichlorophenyl 4-chlorobenzoate (3d)22)
White solid, 147 mg, 88% yield.
2,4,6-Trichlorophenyl 4-ethoxycarbonylbenzoate (3e)22)
Pale yellow solid, 174 mg, 93% yield.
2,4,6-Trichlorophenyl 4-formylbenzoate (3f)22)
Pale yellow solid; 143 mg, 85% yield.
2,4,6-Trichlorophenyl 4-cyanobenzoate (3g)22)
Pale yellow solid, 148 mg, 91% yield.
2,4,6-Trichlorophenyl 4-nitrobenzoate (3h)
1
White solid; 58.8 mg, 34% yield; m.p. 105.0–105.3 °C; H NMR (400 MHz, CDCl3) δ
13
8.44–8.38 (m, 4H), 7.45 (s, 2H) ppm; C NMR (125 MHz, CDCl3) δ 161.3, 151.4, 142.8,
133.3, 132.8, 131.8, 129.6, 128.9, 124.0 ppm; IR (ATR) 1751, 1524, 1254, 1227, 1180,
1134, 1057, 1011, 980, 845, 802, 710, 667, 571, 498, 451 cm–1, Anal. calcd for
C13H6Cl3NO4 C, 45.06; H, 1.75; N, 4.04. found: C, 44.84; H, 1.71; N, 4.10.
2,4,6-Trichlorophenyl 3-methylbenzoate (3i)
1
White solid; 132 mg, 83% yield; m.p. 115.3–116.1 °C; H NMR (400 MHz, CDCl3) δ
13
8.05–8.03 (m, 2H), 7.49–7.40 (m, 4H), 2.45 (s, 3H) ppm; C NMR (125 MHz, CDCl3) δ
163.2, 143.4, 138.8, 135.2, 132.1, 131.1, 129.9, 128.8, 128.7, 127.9, 127.9, 21.4 ppm; IR
(ATR) 1750, 1449, 1270, 1235, 1187, 1139, 1045, 862, 824, 802, 731, 562, 512, 507, 502
cm–1; HRMS (DART) [M+H]+ calcd for C14H10Cl3O2: 314.9746; found 314.9753.
2,4,6-Trichlorophenyl 3-methoxylbenzoate (3j)
White solid; 151 mg, 91% yield; m.p. 60.3–61.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.85
(dt, J = 7.6, 1.2 Hz, 1H), 7.72 (t, J = 1.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.42 (s, 2H),
13
7.22 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H), 3.89 (s, 3H) ppm; C NMR (125 MHz, CDCl3) δ
163.0, 159.9, 143.3, 132.2, 129.9, 129.2, 128.7, 123.1, 121.0, 114.8, 55.6 ppm; IR (ATR)
Chemical and Pharmaceutical Bulletin Advance Publication

1740, 1273, 1234, 1204, 1177, 1138, 1026, 907, 856, 822, 802, 741, 563, 498, 451, 420 cm–
1; HRMS (DART) [M+H]+ calcd for C14H10Cl3O3: 330.9696; found 330.9691.
2,4,6-Trichlorophenyl 2-methylbenzoate (3k)22)
White solid; 38.1 mg, 24% yield.
2,4,6-Trichlorophenyl 2-chlorobenzoate (3l)22)
White solid; 86.9 mg, 52% yield.
2,4,6-Trichlorophenyl 2-cyanobenzoate (3m)
1
White solid; 137 mg, 84% yield; m.p. 156.9–158.3 °C; H NMR (400 MHz, CDCl3) δ
13
8.43–8.41 (m, 1H), 7.94–7.92 (m, 1H), 7.82–7.80 (m, 2H), 7.44 (s, 2H) ppm; C NMR
(125 MHz, CDCl3) δ 160.4, 142.6, 135.4, 134.1, 132.9, 132.7, 132.1, 129.9, 129.7, 128.8,
116.9, 114.0 ppm; IR (ATR) 1753, 1443, 1252, 1227, 1119, 1047, 1028, 853, 820, 789, 760,
727, 685, 658, 565, 552, 527, 509, 501 cm–1; HRMS (DART) [M+H]+ calcd for
C14H7Cl3NO2: 325.9542; found 325.9535.
2,4,6-Trichlorophenyl 1-naphthoate (3n)22)
White solid; 104 mg, 59% yield.
2,4,6-Trichlorophenyl 2-naphthoate (3o)22)
White solid; 156 mg, 89% yield.
2,4,6-Trichlorophenyl nicotinate (3p)22)
White solid; 135 mg, 89% yield.
2,4,6-Trichlorophenyl pyrimidine-5-carboxylate (3q)22)
White solid; 96.6 mg, 64% yield.
2,4,6-Trichlorophenyl thiophene-3-carboxylate (3r)6)
White solid; 140 mg, 89% yield.
2,4,6-Trichlorophenyl thiophene-2-carboxylate (3s)
White solid; 136 mg, 88% yield; m.p. 63.4–63.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.05
(dd, J = 4.0, 0.8 Hz, 1H), 7.73 (dd, J = 4.8, 0.8 Hz, 1H), 7.41 (s, 2H), 7.21 (dd, J = 4.8, 4.0
Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 158.3, 142.9, 135.9, 134.7, 132.3, 130.8,
130.1, 128.7, 128.4 ppm; IR (ATR) 1732, 1562, 1450, 1408, 1354, 1261, 1227, 1138, 1076,
1053, 999, 856, 802, 725, 698, 563, 478, 451, 440 cm–1; HRMS (DART) [M+H]+ calcd for
C11H6Cl3O2S: 306.9154; found 306.9159.
Synthesis of N-((5-bromothiophen-2-yl)methyl)-4-fluorobenzamide (4)
Chemical and Pharmaceutical Bulletin Advance Publication

A solution of 4-fluorobenzoyl chloride (1.06 g, 6.69 mmol, 1.2 equiv) in CH2Cl2 (2.5
mL) was added to a stirred solution of (5-bromothiophen-2-yl)methanamine32) (1.09 g, 5.65
mmol) and iPr2NEt (1.73 mL, 10.2 mmol, 1.8 equiv) in CH2Cl2 (8.2 mL) in 50-mL round
bottomed flask at 0 °C over 30 min, and then the reaction was allowed to warm rt over 19.5
h. The mixture was diluted with CH2Cl2, washed with sat. aq. NaHCO3 (twice), dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude brown solid was
purified by column chromatography (SiO2, hexane/EtOAc = 4/1 to 1/1). Since the resulting
brown solid was found to be contaminated with 4-fluorobenzoic acid, the solid was
dissolved in EtOAc, washed with aq. Na2CO3 (0.5 M), brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to yield 4 as an off white solid (1.51 g, 4.81 mmol,
1
85%). M.p. 116.4–117.1 °C; H NMR (400 MHz, CDCl3) δ 7.80–7.77 (m, 2H), 7.13–7.08
(m, 2H), 6.90 (d, J = 3.2 Hz, 1H), 6.78 (d, J = 4.0 Hz, 1H), 6.48 (br s, 1H), 4.70 (d, J = 6.0
13
1
Hz, 2H) ppm; C NMR (125 MHz, CDCl3) δ 166.4, 165.0 (d, JC–F = 253.8 Hz), 142.6,
130.1 (d, 4JC–F = 2.3 Hz), 129.6, 129.5 (d, 3JC–F = 9.5 Hz), 126.6, 115.8 (d, 2JC–F = 22.8 Hz),
112.0, 39.2 ppm; IR (ATR) 3275, 1624, 1601, 1535, 1501, 1288, 1227, 1204, 1157, 853,
768, 675, 625, 602, 536, 501, 482, 451 cm–1; HRMS (ESI) [M+H]+ calcd for
C12H10BrFNOS: 313.9645; found 313.9645.
Synthesis
of
2,4,6-trichlorophenyl
5-((4-fluorobenzamido)methyl)thiophene-2-carboxylate (5)
Pd(PhCN)2Cl2 (12.2 mg, 31.8 µmol, 1 mol%), Xantphos (36.8 mg, 63.6 µmol, 2 mol%),
4 (1.00 g, 3.18 mmol), 1 (1.43 g, 6.37 mmol, 2.0 equiv), and toluene (6.4 mL) were added
in a 50 mL round-bottomed flask equipped with an argon balloon. The flask was evacuated
and backfilled with Ar three times. DBU (0.95 mL, 6.37 mmol, 2.0 equiv) was added to the
mixture through the septum. The flask was warmed to 80 °C in an oil bath, and the mixture
was stirred for 24 h. After cooling to rt, the mixture was quenched with aq. citric acid (10%
w/v), diluted with CH2Cl2, extracted with CH2Cl2 from the aqueous layer, washed with
H2O, aq. Na2CO3 (0.5 M), and brine, dried over Na2SO4, filtered, and concentrated. The
resulting residue was purified by column chromatography (SiO2, hexane/EtOAc 2/1) to
1
afford 5 (1.35 g, 2.94 mmol, 93%) as a white solid. M.p. 157.5–158.4 °C; H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 4.0 Hz, 1H), 7.83–7.80 (m, 2H), 7.39 (s, 2H), 7.13–7.09 (m,
13
3H), 6.77 (br s, 1H), 4.84 (d, J = 6.0 Hz, 2H) ppm; C NMR (125 MHz, CDCl3) δ 166.5,
Chemical and Pharmaceutical Bulletin Advance Publication

1
4
165.1 (d, JC–F = 253.8 Hz), 158.2, 151.6, 142.8, 136.2, 132.4, 129.94, 129.85 (d, JC–F
=
3
2
2.4 Hz), 129.7, 129.6 (d, JC–F = 9.6 Hz), 128.7, 127.0, 115.9 (d, JC–F = 21.5 Hz), 39.2
ppm; IR (ATR) 3316, 3090, 1748, 1641, 1541, 1499, 1445, 1335, 1254, 1229, 1042, 1013,
851, 816, 766, 729, 505 cm–1; HRMS (DART) [M+H]+ calcd for C19H12Cl3FNO3S:
457.9588; found 457.9578.
Synthesis of (S)-O-benzyl-α-alaninehydroxamic acid TFA salt
TFA
(14.6
mL)
was
added
dropwise
to
a
solution
of
(S)-N-tert-butoxycarbonyl-O-benzyl-α-alaninehydroxamate33) (1.94 g, 6.79 mmol) in
CH2Cl2 (14.6 mL) at 0 °C. The reaction was stirred at 0 °C for 15 min and then at rt for 45
min. The solvents were removed in vacuo. Since the residue did not solidify, the residue
was dissolved in CHCl3 (120 mL) and the solvent was removed in vacuo again to yield the
1
desired salt as a white solid (1.96 g, 6.36 mmol, 94%). M.p. 96.1–98.3 °C, H NMR (500
MHz, D2O) δ 7.32–7.28 (m, 5H), 4.77 (d, J = 11.5 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 3.74
13
(q, J = 7.5 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H) ppm; C NMR (125 MHz, D2O) δ 167.4,
2
1
162.9 (q, JC–F = 35.8 Hz), 134.3, 129.9, 129.3, 128.7, 116.4 (q, JC–F = 289.8 Hz), 78.4,
47.0, 16.5 ppm; IR (ATR) 3096, 3015, 2995, 1695, 1667, 1522, 1431, 1198, 1177, 1134,
1053, 1009, 949, 839, 793, 733, 721, 694, 615 cm–1; MS (DART) [M–CF3CO2]+ calcd for
C10H15N2O2: 195.1134; found 195.1131; [α]D25 –36.5 (c 1.00, H2O).
Synthesis
of
(S)-N-(1-((benzyloxy)amino)-1-oxopropan-2-yl)-5-((4-fluorobenzamido)methyl)-thiophene
-2-carboxamide (6)
(S)-O-Benzyl-α-alaninehydroxamic acid TFA salt (46.2 mg, 0.150 mmol, 1.5 equiv) and
DMAP (0.6 mg, 5.00 µmol, 0.05 equiv) were added to a solution of 5 (45.9 mg, 0.100
mmol) and NEt3 (49 μL, 0.352 mmol, 3.5 equiv) in THF (0.3 mL). The mixture was
warmed to 55 °C, stirred for 44 h, and cooled to rt. The mixture was diluted with EtOAc
and 1 M HCl, extracted with EtOAc from the aqueous layer, washed with brine, dried over
Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative TLC
(SiO2, CHCl3/MeOH/AcOH = 100/10/1) to afford 6 (41.8 mg, 0.0919 mmol, 92%) as a
white solid. M.p. 185.0–185.6 °C; 1H NMR (500 MHz, CD3OD) δ 7.91–7.88 (m, 2H), 7.63
(d, J = 3.5 Hz, 1H), 7.41–7.40 (m, 2H), 7.34–7.29 (m, 3H), 7.21–7.18 (m, 2H), 7.04 (d, J =
4.0 Hz, 1H), 4.83 (s, 2H), 4.72 (s, 2H), 4.36 (q, J = 7.5 Hz, 1H), 1.38 (d, J = 7.5 Hz, 3H)
Chemical and Pharmaceutical Bulletin Advance Publication

13
1
ppm; C NMR (125 MHz, CD3OD) δ 172.0, 168.8, 166.3 (d, JC–F = 249.1 Hz), 164.1,
3
149.6, 138.5, 136.8, 131.6, 131.0 (d, JC–F = 9.5 Hz), 130.6, 130.2, 129.7, 129.4, 127.3,
2
116.5 (d, JC–F = 22.8 Hz), 79.0, 39.6, 17.9 ppm (one carbon signal is missing); IR (ATR)
3260, 1668, 1639, 1612, 1537, 1522, 1503, 1285, 1229, 1157, 847, 737, 694, 669, 625, 606,
557, 530, 486, 457 cm–1; MS (ESI) [M+Na]+ calcd for C23H22FN3NaO4S: 478.1207; found
478.1200; [α]D29 –10.1 (c 0.386, MeOH).
Synthesis
of
(S)-5-((4-fluorobenzamido)methyl)-N-(1-(hydroxyamino)-1-oxopropan-2-yl)thiophene-2-c
arboxamide (7)31)
Compound 6 (34.3 mg, 0.0753 mmol) was dissolved in 1.5 mL of CH2Cl2 and cooled to
0 °C in an ice bath. A solution of BCl3 in CH2Cl2 (1 M, 0.52 mL, 0.52 mmol, 6.9 equiv)
was added dropwise. The reaction mixture was stirred for 1 h at 0 °C. The mixture was then
quenched with 1 M HCl and extracted three times with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting
residue was purified by preparative TLC (SiO2, CHCl3/MeOH 10/1) and by filtering
through a membrane filter (0.45 µm pore size) to afford 7 (13.6 mg, 0.037 mmol, 49%) as a
white solid. M.p. 106.0–107.4 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.65 (bs, 1H), 9.24 (t,
J = 5.5 Hz, 1H), 8.82 (bs, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.96–7.93 (m, 2H), 7.72 (d, J = 4.0
Hz, 1H), 7.31 (t, J = 8.8 Hz, 2H), 7.02 (d, J = 3.5 Hz, 1H), 4.61 (d, J = 5.5 Hz, 2H), 4.34–
4.31 (m, 1H), 1.28 (d, J = 7.5 Hz, 3H) ppm; 13C NMR (125 MHz, DMSO-d6) δ 169.1,
165.2, 164.0 (d, 1JC–F = 246.9 Hz), 160.8, 148.0, 138.1, 130.4 (2 signals), 130.0 (d, 3JC–F
=
2
8.4 Hz), 128.5, 125.9, 115.4 (d, JC–F = 21.5 Hz), 46.6, 38.2, 18.2 ppm; IR (ATR) 3250,
3213, 3071, 2924, 1624, 1602, 1541, 1499, 1609, 1287, 1231, 1159, 1026, 849, 820, 766,
623 cm–1; MS (ESI) [M+Na]+ calcd for C16H16FN3NaO4S: 388.0743; found 388.0757;
[α]D25 +4.4 (c 0.25, MeOH).
Acknowledgements This study was partly supported by JSPS KAKENHI Grant
Numbers 15H04634 and 15K18834, the Uehara Memorial Foundation, the Takeda Science
Foundation, the Tokyo Biochemical Research Foundation, and the Platform Project for
Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery,
Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports,
Chemical and Pharmaceutical Bulletin Advance Publication

Science and Technology (MEXT) and Japan Agency for Medical Research and Development
(AMED).
Conflict of Interest The authors declare no conflict of interest.
Supplementary Material The online version of this article contains supplementary
materials (copies of NMR spectra of newly obtained compounds).
Chemical and Pharmaceutical Bulletin Advance Publication

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