Synthetic route for the preparation of 2-Hydroxy- N -[1-(2- hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides

Full text of DOI:10.1021/cc900168s

414
J. Comb. Chem. 2010, 12, 414–416
(AA; neutral Gly, Ala, Val, Phe; basic Trp and unnatural
cyclohexylalanine and tert-butyl glycine) by benzyloxycar-
bonyl (CBZ) or tert-butyloxycarbonyl (BOC) groups 2. N,N′-
Dicyclohexylcarbodiimide (DCC) was used as an optimal
activation agent in dry dimethylformamide (DMF). The
N-protected AA esters of SAL 3 were isolated in high purity
by crystallization from ethyl acetate-hexane after filtration
of N,N′-dicyclohexylurea and vacuum evaporation of DMF.3a
Synthetic Route for the Preparation of
2-Hydroxy-N-[1-(2-hydroxyphenylamino)-
1-oxoalkan-2-yl]benzamides
Alesˇ Imramovsky´,*,† Juana M. Fe´rriz,‡ Karel Pauk,†
Martin Kra´tky´,‡ and Jarmila Vinsˇova´‡
Institute of Organic Chemistry and Technology,
Faculty of Chemical Technology, UniVersity of
Pardubice, 532 10 Pardubice, the Czech Republic, and
Department of Inorganic and Organic Chemistry,
Faculty of Pharmacy, Charles UniVersity, 500 05
Hradec Kra´loVe´, the Czech Republic
Table 1. List of Prepared Compounds 4 and 5
ReceiVed October 26, 2009
2-Hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-
yl]benzamides 5 are original organic compounds containing
two amidic functions and therefore are known as “diamides”.
In the recent past, our research group has found them to be
potential antimicrobial agents,1 presenting in Vitro antimy-
cobacterial activity in the range of 62.5 to 8 µmol/L against
Mycobacterium tuberculosis (M. tuberculosis) and against
some nontuberculosis strains, such as M. aVium and M.
kansasii. These compounds were also tested for their in Vitro
antifungal activity, showing interesting results for only a few
members of the mentioned group of compounds (e.g., 0.49
µmol/L after 24/48 h for 5e against Trichophyton menta-
grophytes or 5bb and 5cc 3.9/7.81 and 1.95/3.9 µmol/L
against Candida krusei strain). Furthermore, Shibasaki and
co-workers2 have published the synthesis of the diamide (R)-
2-hydroxy-N-[1-(2-hydroxyphenylamino)-3-methyl-1-oxobu-
tan-2-yl]benzamides (Scheme 1) as a promising ligand for
the amination of succinimide in the catalytic asymmetric
synthesis of AS-3201. The compound marked AS-3201 was
identified as a structurally novel aldose-reductase inhibitor
used in the treatment of diabetic disorders.2
In this context, the aim of this article was to describe an
efficient and novel synthesis for this kind of “diamides”.
Initially, 2-hydroxy-N-(1-(oxo-(phenylamino)-alkan-2-yl)-
benzamides 5 were prepared as a part of our ongoing search
for new antituberculosis active molecules of salicylanilide
esters.3 Their synthesis started from several substituted
salicylanilides (SAL) 1, which were selected according to
previous results showing high in Vitro activity against M.
tuberculosis.4 They were routinely prepared using phospho-
rus trichloride (PCl3) as a dehydrating agent in chlorobenzene
(Ph-Cl), a well-known synthetic route. By using microwave
irradiation (MW), the reaction time was shortened from
several hours to minutes (see Scheme 2).5
yield of
4 (%)
yield of
5 (%)
compd R1
R2
R3
compd
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4-Cl 4-Cl
4-Cl 4-Cl
(R)-CH3
89
97
92
92
95
NP
91
93
97
93
69
67
NP
87
89
90
90
45
90
90
88
77
96
89
96
90
90
59
89
78.5
NI
NI
97
73
98
89
93
90
92
94
85
83
92
97
96
91
NI
94
94
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
5w
5x
5y
5z
5aa
5bb
5cc
5dd
5ee
5ff
5gg
5hh
5ii
49a
39a
57a
44a
61a
NP
56a
50a
39a
32a
27b
23b
NP
53a
40a
23b
34b
32b
43a
88c
46a
39a
60a
75c
36c
89c
65c
95c
91c
85c
76c
69c
82c
88c
93c
91c
93c
93c
68c
68c
64b
73a
69a
48a
40b
40b
41c
66c
74c
(S)-CH(CH3)2
(R)-CH(CH3)2
(S)-CH2-phenyl
(R)-CH2-phenyl
(R)-CH3
(S)-CH(CH3)2
(R)-CH(CH3)2
(S)-CH2-phenyl
(R)-CH2-phenyl
H
4-Cl 4-Cl
4-Cl 4-Cl
4-Cl 4-Cl
4-Cl 4-Br
4-Cl 4-Br
4-Cl 4-Br
4-Cl 4-Br
4-Cl 4-Br
4-Cl 4,3-diCl
4-Cl 4,3-diCl (S)-CH3
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4-Cl 4,3-diCl (R)-CH3
4-Cl 4,3-diCl (S)-CH(CH3)2
4-Cl 4,3-diCl (R)-CH(CH3)2
4-Cl 4,3-diCl (S)-CH2-phenyl
4-Cl 4,3-diCl (R)-CH2-phenyl
4-Cl 3-Cl
4-Cl 3-Cl
4-Cl 3-Cl
4-Cl 3-Cl
4-Cl 3-Cl
4-Cl 3-Cl
4-Cl 3-Cl
4-Cl 4-CH3
4-Cl 4-CH3
4-Cl 4-CH3
4-Cl 4-CH3
4-Cl 4-CF3
4-Cl 4-CF3
4-Cl 3-CF3
4-Cl 3-CF3
4-Cl 4-Br
4-Cl 4-NO2
H
(S)-CH3
(R)-CH3
(S)-CH(CH3)2
(R)-CH(CH3)2
(S)-CH2-phenyl
(R)-CH2-phenyl
(S)-CH3
(S)-CH(CH3)2
(S)-CH2-phenyl
(R)-CH2-1H-indol-3-yl
(S)-CH(CH3)2
(R)-CH2-1H-indol-3-yl
-CH2-cyclohexyl
-C(CH3)3
4y
4z
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
4ii
4jj6
4kk6
4ll6
-CH2-cyclohexyl
(S)-CH(CH3)2
4-Cl 4-OCH3 (S)-CH(CH3)2
H
H
H
4-Cl
(S)-CH(CH3)2
5jj6
5kk6
5ll6
5 mm
5nn
5oo
5pp
5qq
5rr
5ss
5tt
5uu
5vv
5ww
4-OCH3 (S)-CH(CH3)2
4-CH3
(S)-CH(CH3)2
(S)-CH(CH3)2
(S)-CH2-phenyl
(S)-CH3
4 mm 5-Cl 4-Br
4nn
4oo
4pp
4qq
4rr
4ss
5-Cl 4-Br
5-Cl 4-Cl
5-Cl 4-Cl
5-Cl 4-Cl
5-Cl 4-Cl
5-Cl 4-Cl
5-Cl 4-Cl
(R)-CH3
(S)-CH(CH3)2
(R)-CH(CH3)2
(S)-CH2-phenyl
(R)-CH2-phenyl
The first step in the diamide 5 preparation was the
esterification of SAL 1 with N-protected R or S amino acids
4tt
4uu
4vv
4ww
5-Cl 4,3-diCl (S)-CH3
5-Cl 4,3-diCl (S)-CH(CH3)2
5-Cl 4,3-diCl (S)-CH2-phenyl
* To whom correspondence should be addressed. E-mail: ales.imramovsky@
upce.cz. Phone: +420 466037739. Fax: +420 466038004.
† University of Pardubice.
a Column chromatography (yields). b Chromatotron (yields). c Gradient
column chromatography. NP: the starting esters were not prepared, thus
following reactions were not carried out. NI: not isolated.
‡ Charles University.
10.1021/cc900168s  2010 American Chemical Society
Published on Web 04/30/2010

Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 415
Scheme 1. (R)-2-Hydroxy-N-[1-(2-hydroxyphenylamino]-3-methyl-1-oxobutan-2-yl)benzamide Synthesis: The Shibasaki
Pathwaya
a Reaction conditions: (a) EDC · HCl, HOBt, Et3N, CH2Cl2, 0 °C to rt; (b) 4M HCl/dioxane, 0 °C to rt; (b) O-acetylsalicyloyl chloride, Et3N, CH2Cl2,
0 °C to rt; (d) K2CO3, MeOH/CH2Cl2, rt; (e) Pd/C, H2, MeOH/CH2Cl2, rt.
Scheme 2. MW Synthesis of SAL 1
SAL-AA esters 4 as white hygroscopic solids in almost
quantitative yields, for details see Table 1 and ref 6.
The rearrangement of SAL-AA esters after the amino
group deprotection by triethylamine yielded the final products
5. The proposed mechanism of this rearrangement was
recently published.7 The structure of 5 was unequivocally
Prepared esters are the starting compounds for our reaction.
corroborated by HMBC 2D NMR experiments (Scheme 3).
Their synthesis and possible problems in their preparation
were recently published.3
The N-deprotection of the amino group failed under
generous conditions of hydrogenolysis (H2/Pd); the ester
linkage was found unstable even if different reaction condi-
tions and solvents were used (temperature modification,
toluene, ethyl acetate and methanol as solvents). Amino
group liberation was finally realized by using 33% solution
of hydrogen bromide in glacial acetic acid. Diethyl ether
addition precipitated the appropriate hydrobromide salts of
The proposed mechanism of rearrangement is based on
the isolation and identification of dehydrated form of reaction
intermediate 2-(5-chloro-2-hydroxyphenyl)-1-(3-chlorophe-
nyl)-4-isopropyl-1H-imidazol-5(4H)-one by 2D NMR and
X-ray analysis. The mechanism is carefully described in our
recent publication. For further information, see Scheme 4
and ref 7.
This rearrangement has been found general for AA esters
3 and was observed independently on the AA type or electron
Scheme 3. Synthesis of HBr Salts of N-Protected Esters and Their Subsequent Rearrangement
Scheme 4. Proposed Mechanism of Rearrangement7
Scheme 5. Leuch Amino Acid Condensation

416 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Reports
effects of substituents presented on salicylic/anilide moiety,
respectively, as well as the kind of protection of AA amino
group.
The same kind of “diamide” 5 was obtained by one step
synthesis when Leuch anhydride of amino acid 6 (i.e., Phe,
Ala; 5z, 5dd) was condensed with potassium or sodium salt
of salicylanilides (see Scheme 5).1 This pathway needs the
previous Leuch anhydride of AA preparation.8
In conclusion, N-deprotection of SAL-AA esters gave a
series of original 2-hydroxy-N-[1-(2-hydroxyphenylamino)-
3-methyl-1-oxobutan-2-yl]benzamides 5 with potential an-
timycobacterial and antifungal activity.
In contrast to building up the diamide step by step from
N-Boc amino acid, O-protected 2-aminophenol, and O-
acetylsalicyloyl chloride, here, we are proposing a different
method based on the new salicylanilide rearrangement. This
approach includes less synthetic steps, as well as wide range
of substituents variability on the both benzene rings and alkyl
part of the final molecules.
References and Notes
(1) Imramovsky´, A.; Vinsˇova´, J.; Fe´rriz, J. M.; Kunesˇ, J.; Pour,
M.; Dolezˇal, M. Tetrahedron Lett. 2006, 47, 5007–5011.
(2) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342–11343.
(3) (a) Imramovsky´, A.; Vinsˇova´, J.; Fe´rriz, J. M.; Buchta, V.;
Jamp´ılek, J. Bioorg. Med. Chem. Lett. 2009, 19, 348–351. (b)
Imramovsky´, A.; Vinsˇova´, J.; Fe´rriz, J. M.; Dolezˇal, R.;
Jamp´ılek, J.; Kaustova´, J.; Kunc, F. Bioorg. Med. Chem. 2009,
17, 3572–3579.
(4) Waisser, K.; Buresˇ, O.; Holy´, P.; Kunesˇ, J.; Oswald, R.;
Jira´skova´, L.; Pour, M.; Klimesˇova´, V.; Kubicova´, L.; Kaustova´,
J. Arch. Pharm. (Weinheim, Ger.) 2003, 336, 53–71.
(5) (a) Equivalent amount of substituted salicylic acid and aniline
were mixed in Ph-Cl. Phosphorus trichloride (0.5 equiv) was
added. The mixture was then irradiated in MW reactor
MicroSynth (450W) for 20 min to reflux. Then, the reaction
mixture was cooled, and the crude product collected by
filtration, followed by recrystallization from acetone to obtain
pure product. (b) Colombo, M.; Bossolo, S.; Aramini, A.
J. Comb. Chem. 2009, 11, 335–337.
(6) General literature procedure3b for compound 3: N-CBZ or
N-BOC protected 2-amino acid 2 (10 mmol) and substituted
salicylanilide 1 (10 mmol) were dissolved in dry DMF (45 mL).
The solution was cooled to -15 °C and N,N′-dicyclohexylcar-
bodiimide (DCC, 11 mmol) was added in three portions during
1 h. The mixture was stirred for 3 h at the same temperature
and stored at +4 °C for 20 h. The precipitate of N,N′-
dicyclohexylurea was removed by filtration, and the solvent
was evaporated in vacuo. The crude product 3 was purified by
crystallization from ethyl acetate-hexane.
Acknowledgment. This work was financially supported
by the Ministry of Education, Youth and Sports of the Czech
Republic (MSM 002 162 7501 and MSM 002 162 0822)
and IGA NS 10367-3.
Note Added after ASAP Publication. The Acknowl-
edgments were modified in the version of this paper
published ASAP April 30, 2010; the corrected version
published ASAP May 7, 2010.
(7) Vinsˇova´, J.; Imramovsky´, A.; Kra´tky´, M.; Fe´rriz, J. M.; Pala´t,
K.; Lycˇka, A.; Ru˚zˇicˇka, A. Tetrahedron Lett. 2010, 51, 23–
26.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for prepared compounds. This
information is available free of charge via the Internet at
http://pubs.acs.org.
(8) Daly, W. H.; Poche´, D. Tetrahedron Lett. 1988, 29, 5859–5862.
CC900168S