N-[(diphenoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole as a versatile reagent for synthesis O-alkylhydroxamic acids

Article abstract of DOI:10.1002/jhet.5570450406

(Chemical Equation Presented) Highly efficient reagent, N-[(diphenoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole was synthesized and its applicability was demonstrated for the synthesis of O-alkyl hydroxamic acids. The efficiency of the reagent was evaluate

Full text of DOI:10.1002/jhet.5570450406

Jul-Aug 2008
981
N-[(Diphenoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole as a
Versatile Reagent for Synthesis O-Alkylhydroxamic Acids
Nagnnath D. Kokare a, b, Devanand B. Shinde b *
a Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad-431004
(MS), India
b Wockhardt Research Centre, Aurangabad-431210 (MS), India
Received March 21, 2007
N
N
O
O
P
OPh
O
O
OPh
O
N
Bn
OH
H
Bn
NH2
N
N
O
O
O
H
Bn
NH2
H
N
O
O
N
Boc
N
Bn
OH
Boc
H
N
N
O
O
P
OPh
OPh
Highly efficient reagent, N-[(diphenoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole was synthesized
and its applicability was demonstrated for the synthesis of O-alkyl hydroxamic acids. The efficiency of the
reagent was evaluated through the synthesis of range of O-alkyl hydroxamic acids from aromatic
carboxylic acids as well as N-protected amino acids. The enatiomeric purity of synthesized compounds was
measured using chiral HPLC and the degree of racemization that occurred was found to be negligible.
J. Heterocyclic Chem., 45, 981 (2008).
INTRODUCTION
acid and O-alkyl hydroxylamines [10]. Although some of
these methods are quite efficient for the preparation
substituted hydroxamic acids, these methods suffered from
some drawbacks such as instability, toxicity, high volatility
of acylating agents like acid chloride or the activated esters,
high cost and difficult purification which limit their
applications. Hence, the development of a convenient and
practical method is important for the efficient preparation
of hydroxamic acids from carboxylic acids. In connection
with our ongoing research to develop the simple and
efficient methods for synthesis of heterocyclic compounds
[11], we are gratified to present the simple and efficient
method for the synthesis of O-alkylhydroxamic acids using
Hydroxamic acid analogues are important targets for the
medicinal chemists because of the intrinsic chelating
interactions of this functional group with Zn++ at the active
site of metalloprotiens [1,2]. Also hydroxamic acids are
important in many chemotherapeutic agents such as the
succinate-based
matrix
metalloprotienases (MMP)
inhibitors [3], the class I/II histone deacetylase (HDAC)
inhibitors [4] and iron-containing antibiotics [5]. Literature
reveals, the various methods for the preparation of
hydroxamic acids starting from carboxylic acids or their
derivatives [6] and N-acyloxazolidinones [7].
The
reagent
benzimidazole.
N-[(diphenoxyphosphoryl)oxy]-2-phenyl-1H-
conversion of ester to hydroxamic acid is generally
achieved by two step preparation, firstly salt of hydroxyl
amine followed by addition of ester in alcohol solvent [8]
or activation of acid using acyl chloride or mixed anhydride
and quenching with O-protected hydroxyl-amine analogues
[9]. Recently, we had developed the coupling reagent N-
[(diethoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole for
synthesis of O-alkyl hydroxamic acids from coupling of
In previous work, the reagent, N-[(diphenoxyphos-
phoryl)oxy]-2-phenyl-1H-benzimidazole was synthesized
and its application was demonstrated for the peptide
coupling reactions with minimal racemization [11a]. In
present article, we had explored the application of reagent
for synthesis of the various O-alkylhydroxamic acids. The

982
N. D. Kokare and D. B. Shinde
Vol 45
Table 1
Synthesis of different O-alkyl hydroxamic acids using reagent 2.
Reaction
Mp °C
Entry
No.
R1
R2
Bn
Product (3a – 3j)
time (min)
Yield
(%)
Found
Reported [Ref.]
102-104 11
1
50
96
101 -103
O
O
N
H
3a
O
2
Bn
50
92
126 - 127
128 13
O
N
H3C
H
H3C
MeO
O2N
3b
O
3
4
Bn
Bn
45
30
92
98
109 - 110
165 - 166
110 -11111
O
N
MeO
H
3c
O
166 -167 11
O
N
O2N
H
3d
5
6
7
8
Bn
Bn
Bn
Bn
40
60
50
50
95
87
85
91
157 - 158
99 - 100
100 - 110
73 -74
15813
O
O
N
Cl
H
Cl
3e
O
99 - 100 11
99 - 10111
72 - 73 11
O
N
H
3f
O
O
N
O
H
O
3g
O
O
N
H
N
N
3h
9
Ethyl
Allyl
45
50
88
93
80 - 81
81 - 82 11
O
O
N
H
3i
10
50 - 51
50 14
O
O
N
H
3j

Jul-Aug 2008
N-[(Diphenoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole as a Versatile Reagent
983
reagent was synthesized according to the reported
procedure [12], which involves synthesis of N-hydroxy-
benzimidazole (1) from the reaction of ortho-nitro aniline
with benzyl bromide using sodium hydride base. The
benzyl deprotection was carried out using 10% Pd/C as
catalyst. The coupling reagent N-[(diphenoxy-phos-
phoryl)oxy]-2-phenyl-1H-benzimidazole (2) was synthe-
sized by treating compound 1 with diphenyl phosphoro-
chloridate and triethylamine base in dichloromethane
solvent (Scheme 1).
Using the similar reaction conditions, different O-alkyl
hydroxamic acids (Scheme 2) were synthesized and the
results are summarized in Table 1. All synthesized
compounds were characterized by mass, IR, and 1H NMR.
From the results obtained, the acids with electron
withdrawing-substituents
like
nitro
(3d)
took
comparatively less reaction time for the completion of
reaction than the acids with the electron-donating like
methyl (3b) or without the substituents (3a, 3i, and 3j).
The reagent 2 shows the superiority over the existing
methods regarding the yields and purification method.
Especially the 4-nitro N-benzyloxy benzamide (3d) was
isolated with better yield (98%) than the reported methods
in the literature (37%) [13]. The easy work up was the
more advantageous aspect of this method, which includes
only the acid-base treatment and triturating with the
RESULTS AND DISCUSSION
Initially we focused our efforts on the synthesis of N-
hydroxy benzamide from benzoic acid and hydroxylamine
hydrochloride. To achieve this, although we made
different attempts with different variations regarding the
solvent, temperature, bases and their equivalents,
unfortunately the formation of required compound was
not observed. So, we concentrated our efforts on the
synthesis of O-alkylhydroxamic acids. Interestingly, by
using the regent 2, we were able to synthesize O-
benzyloxy benzamide in 82% yield in standardized
reaction conditions, which includes the use of three
equivalent of diisopropylethylamine base and DMF. Also
to improve the yield, a new method was developed in
which the reagent 2 was synthesized and used in-situ for
the coupling reaction of carboxylic acid and O-alkyl
hydroxylamines. The isolated yield of O-benzyloxy
benzamide was improved up to 96% by using in-situ
synthesized reagent 2.
Table
Synthesis of different O-benzyl hydroxamic acids from N-protected
amino acids.
Entry No
1
Product
Yielda
(%)
%ee b
94.7
86
82
93
O
H
N
O
Boc
N
H
4a
2
3
91.3
96.4
O
H
N
O
Boc
N
H
Scheme 1
4b
NH2
N
N
a
O
b
O
NO2
N
H
O
N
bn
Boc
N
N
4c
N
c
4
5
90
89
95.5
91.9
O
H
N
N
O
O
O
OH
Cbz
N
H
P
OPh
PhO
4d
Synthesis of Reagent
O
H
N
(a) NaH, BnBr, THF, 80 °C, 4 hrs; (b) 10% Pd/C, H2, methanol, 15 min;
(c) (PhO)2P(O)Cl, (Et)3N, dichloromethane, 30 min, 0 °C.
O
Cbz
N
H
4e
Scheme 2
O
suitable solvent to get the pure compound. During the
work up, N-hydroxy-2-phenylbenzimidazole (1) could be
easily isolated by acid base treatment and could be re-
used for synthesis of reagent 2. To illustrate the efficiency
of recovered 1, N-benzyloxybenzamide was synthesized
using the reagent synthesized from recovered 1 and that
2
O
O
R1
OH
R1
N
R2
R2-ONH2
H
3a - 3j
Synthesis of O-alkyl hydroxamic acids

984
N. D. Kokare and D. B. Shinde
Vol 45
gave the constant better yields (1st recovered 1 - 92%
yield, 2nd recovered 1 - 91% yield and 3rd recovered 1 -
91% yield).
EXPERIMENTAL
1H NMR spectra were recorded on a 400 MHz Varian-Gemini
spectrometer and are reported as parts per million (ppm)
downfield from a tetramethylsilane internal standard. The
following abbreviations are used; singlet (s), doublet (d), triplet
(t), quartet (q), multiplate (m) and broad (br). Mass spectra were
taken with Micromass - QUATTRO-II of WATER mass
spectrometer. HPLC was performed using Zorbax SB-C18
reverse phase column (0.46 X 25 cm) on Shimadzu instrument
equipped with an automatic injector with UV-PDA detector.
Detection was carried out at 254 nm. The mobile phase consists
of 0.05 % TFA and acetonitrile (1:1, V/V). The products were
eluted at flow rate of 1 mL/min using isocratic method. Flash
column chromatography was performed with 300-400 meshes
silica gel and analytical thin layer chromatography was
performed on precoated silica gel plates (60F-254) with system
(v/v) indicated. Melting points were determined in capillary
tubes and are uncorrected.
The applicability of reagent 2 was also demonstrated
for coupling of O-benzyl hydroxylamine with N-protected
amino acids (4a-4e). The results obtained are summarized
in Table 2. For these reactions, moderate to good yields
were obtained and were in the range of 82% to 93%. The
extent of racemization occurred was measured using the
chiral HPLC. The percentages of enantiomeric excess (ee
%) obtained were in the range of 91.3% to 96.4%, which
proves the efficiency of coupling reagent 2 for optically
active substrates.
The optical rotations of some of the synthesized
compounds were measured and compared with the
corresponding reported values in literature. In case of
(1-Benzyloxycarbamoyl-ethyl) carbamic acid tert-butyl
ester (4a), the reported specific rotation was [ꢀ]D = -58.3°
(c = 0.1, CHCl3) [14] and in similar conditions, for our
product found -58.2. The observed optical rotation
matched well with corresponding reported values in
literature and hence supporting for the lower
racemization.
Synthesis of N-[(diphenoxyphosphoryl)oxy]-2-phenyl-1H-
benzimidazole (2). A solution of N-hydroxy-2-phenylbenz-
imidazole (0.42 g, 0.02 mol) and triethyl amine (0.70 mL, 0.05
mol) was stirred in DCM (2.5
mL) and the diphenyl
phosphorochloridate (0.21 mL, 0.024 mol) was added at 0 ° C.
The reaction mixture was stirred till the completion of reaction
(TLC). Then DCM was evaporated and the residue was stirred
with pentane and decanted. The remaining residue was stirred
with diethyl ether and decanted three times. The combined
diethyl ether was concentrated to give the title compound 2 as a
white solid. Yield – 624 mg, (71%); mp 93 - 95 ° C (dec.); IR -
(Nujol, cm –1) 2930, 1244, 1105, and 1018; H NMR (CDCl3) ꢁ
7.2 - 7.4 (m, 13H), 7.6 (d, J=8.0 Hz, 2H), 7.8 (d, J=8.2 Hz, 2H),
+
8.2 (d, J=8.2 Hz, 2H); EIMS - 443
The intermediate (5) formed from the reaction of
benzoic acid and O-benzyl hydroxylamine was isolated
1
(Scheme 3) and characterized using mass, IR and H
NMR spectroscopy. The formation of intermediate 5
suggest the probable mechanism, that firstly benzoic acid
reacts with reagent 2 to give the active ester 5 and later
with the O-benzylhydroxylamine to give the product.
1
(M ); Anal. Cald for
C25H19N2O4P: C, 67.87; H, 4.33; N, 6.33. Found: C, 67.81; H,
4.41; N, 6.30.
Scheme 3
General procedure for in-situ synthesis O-alkylhydrox-
amic acids. A solution of N-hydroxy-2-phenylbenzimidazole
(0.02 mol) and DIPEA (0.07 mol) was stirred in DMF and the
diphenyl phosphorochloridate (0.024 mol) was added with
cooling. The reaction mixture was stirred for 10 min and the
carboxylic acid (0.016 mol) was added and reaction mixture was
stirred for 10 min at 0 °C for active ester formation. Then O-
alkyl hydroxylamine (0.03 mol) was added and mixture stirred
at room temperature till completion of reaction (TLC). Then,
saturated aq. NaCl (20 mL) solution was added, and the mixture
was extracted with ethyl acetate (15 mL ꢀ 2). The organic layer
was washed with 2 N HCl (15 mL), saturated NaHCO3 (15 mL)
and finally water (2 ꢀ 20 mL). The organic layer was dried over
sodium sulphate, filtered and evaporated to give the
corresponding O-alkyl hydroxamic acids.
O
O
2
BnONH2
N
O
OH
N
5
O
N
N
O
+
N
H
OH
3a
2
1
N-Benzyloxybenzamide (3a). Mp 102 - 104 °C; H NMR
Probable mechanism and isolation of intermediate 5.
(CDCl3) ꢁ = 5.01(s, 2H), 7.3 - 7.4 (m, 5H), 7.5(m, 3H), 7.65 (d, J
= 8.2 Hz, 2H), 8.87 (br s, 1H); EIMS - 228 (M +); Anal. Cald for
C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 74.23; H,
5.64; N, 6.21.
In conclusion, the reagent 2 was synthesized easily
from cheap starting materials and used in-situ for
synthesis of O-alkylhydroxamic acids. The advantages of
this coupling reagent are their scalability, higher yields
and use of cheap and easily available starting materials for
synthesis of reagent. Also minimum racemization
occurred during the synthesis of O-benzyl protected
hydroxamic acids with optical active substrates.
N-Benzyloxy-4-methylbenzamide (3b). Mp 128 - 129 °C;
1H NMR (CDCl3) ꢁ = 2.34(s, 3H), 4.9(s, 2H), 7.3 - 7.4 (m, 7H),
+
7.65 (d, 2H), 10.2 (br s, 1H); EIMS - 241 (M ); Anal. Cald for
C15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.76; H,
5.96; N, 6.19.
N-Benzyloxy-4-methoxybenzamide (3c). Mp 110 - 111 °C;
1H NMR (CDCl3) ꢁ = 3.8 (s, 3H), 5.0 (s, 2H), 6.82 (d, 2H), 7.35

Jul-Aug 2008
N-[(Diphenoxyphosphoryl)oxy]-2-phenyl-1H-benzimidazole as a Versatile Reagent
985
- 7.4 (m, 5H), 7.65 (d, 2H), 10.15 (br s, 1H); EIMS – 258 (M +);
Anal. Cald for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C,
69.86; H, 6.11; N, 5.42.
Benzyl-1-(benzyloxycarbamoyl)-ethylcarbamate (4e). Mp
1
121- 122 °C; H NMR (CDCl3) ꢀ = 1.32(d, J= 6.6 Hz, 3H), 4.1
(br s, 1H), 4.65 (m, 1H), 4.8 (s, 2H), 5.0 (s, 2H), 5.22 (br s, 1H),
7.33 - 7.4 (m, 10H); EIMS - 329 (M +); Anal. Cald for
C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C, 65.83; H,
6.11; N, 8.54.
1
N-Benzyloxy-4-nitrobenzamide (3d). Mp 166 - 167 °C; H
NMR (CDCl3) ꢀ = 5.1(s, 2H), 7.35 - 7.4 (m, 5H), 7.9 (d, 2H),
+
8.25 (d, 2H), 10.3 (br s, 1H); EIMS - 273 (M ); Anal. Cald for
Benzoic acid 2-phenyl-benzoimidazol-1-yl ester (5). Mp
234-235 °C; H NMR (400 MHz, CDCl3): ꢀ = 7.2 (m, 2H),
7.4(m, Hz, 3H), 7.5-7.7 (m, 7H), 8.2 (d, J = 8.2 Hz, 2H); MS
(EI, 70 eV): m/z = 315 [M+H]+; Anal. Cald for C20H14N2O2: C,
76.42; H, 4.49; N, 8.91. Found: C, 76.27; H, 4.51; N, 8.90.
C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.71; H,
4.48; N, 10.23.
1
1
N-Benzyloxy-4-chlorobenzamide (3e). Mp 158 - 159 °C; H
NMR (DMSO-d6) ꢀ = 5.0(s, 2H), 7.4 (m, 5H), 7.55 (d, 2H), 7.80
+
(d, 2H), 11.85 (br s, 1H); EIMS - 262 (M ); Anal. Cald for
C14H12ClNO2: C, 64.25; H, 4.62; N, 5.35. Found: C, 64.19; H,
4.67; N, 5.23.
N-Benzyloxy-3-phenylacrylamide (3f). Mp 99 - 100 °C; H
Acknowledgement. The authors are thankful to the Head,
Department of Chemical Technology, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad- 431004 (MS), India for
providing the laboratory facility.
1
NMR (CDCl3) ꢀ = 4.95 (s, 2H), 6.54 (d, J =15.0 Hz, 1H), 7.35
(m, 6H), 7.44 (m, 4H), 7.69 (d, J =15.0 Hz, 1H), 10.25 (br s,
+
1H); EIMS - 254 (M ); Anal. Cald for C16H15NO2: C, 75.87; H,
5.97; N, 5.53. Found: C, 76.01; H, 5.92; N, 5.60.
REFERENCES AND NOTES
Furan-2-carboxylic acid benzyloxy-amide (3g). Mp 99 -
1
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(m, 1H), 7.4 (m, 6H), 10.35 (br s, 1H); EIMS - 218 (M +); Anal.
Cald for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C,
66.71; H, 4.98; N, 6.49.
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1
N-Benzyloxy-nicotinamide (3h). Mp 72 - 73 °C; H NMR
(CDCl3) ꢀ = 5.02 (s, 2H), 7.35 (m, 6H), 8.12 (d, 1H), 8.65 (d,
1H), 8.92 (s, 1H), 10.2 (br s, 1H); EIMS - 229 (M +); Anal. Cald
for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.45; H,
5.28; N, 12.34.
1
N-Ethoxybenzamide (3i). Mp 60 - 61 °C; H NMR (CDCl3)
ꢀ = 1.2(t, 2H), 4.0(t, 3H), 7.45 - 7.5 (m, 3H), 7.7 (d, 2H), 9.8 (br
+
s, 1H); EIMS - 166 (M ); Anal. Cald for C9H11NO2: C, 65.44;
H, 6.71; N, 8.48. Found: C, 65.80; H, 6.69; N, 8.41.
1
N-Allyloxybenzamide (3j). Colorless oil; H NMR (CDCl3)
ꢀ = 4.4(d, 2H), 5.2 - 5.3(m, 2H), 6.1(m, 1H), 7.5(m, 3H), 7.65
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+
(d, 2H), 9.95 (br s, 1H); EIMS - 178 (M ); Anal. Cald for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.48; H,
6.30; N, 8.93.
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1
Mp 99 - 100 °C; H NMR (CDCl3) ꢀ = 1.31(d, J=6.8 Hz, 3H),
1.42 (s, 9H), 4.08 (br s, 1H), 4.69(m, 1H), 4.89 (s, 2H), 5.19 (br
+
s, 1H), 7.33 - 7.38 (m, 5H); EIMS - 295 (M ); Anal. Cald for
C15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found: C, 61.33; H,
7.51; N, 9.49.
tert-Butyl-1-(benzyloxycarbamoyl)-2-methylpropyl car-
bamate (4b). Mp 83 - 84 °C; 1H NMR (CDCl3) ꢀ = 0.98 (d, 6H),
1.45 (s, 9H), 2.2(m, 1H), 4.3(dd, 1H), 4.08 (br s, 1H), 4.89 (s,
+
2H), 5.19 (br s, 1H), 7.33 - 7.38 (m, 5H); EIMS - 323 (M );
Anal. Cald for C17H26N2O4: C, 63.33; H, 8.13; N, 8.69. Found:
C, 63.41; H, 7.98; N, 8.73.
tert-Butyl-2-(benzyloxycarbamoyl)pyrrolidine-1-carbox-
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1
ylate (4c): Low melting solid; H NMR (CDCl3) ꢀ = 1.45 (s,
9H), 1.6-1.8 (m, 4H), 3.35 (t, 2H), 4.29 (t, 1H), 4.89 (s, 2H),
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[11] [a] Kokare, N. D.; Nagawade, R. R.; Rane, V. P.; Shinde, D.
B. Synthesis, 2007, 766; [b] Bahekar, S. S.; Shinde D. B. Tetrahedron
Lett. 2004, 45, 7999; [c] Bahekar, S. S.; Kotharkar, S. A.; Shinde D. B.
Mendeleev. Commun; 2004, 210; [d] Kotharkar, S. A.; Jadhav, M. R.;
+
5.19 (br s, 1H), 7.5 (m, 5H); EIMS - 321(M ); Anal. Cald for
C17H24N2O4: C, 63.73; H, 7.55; N, 8.74. Found: C, 63.58; H,
7.51; N, 8.74.
Benzyl-1-(benzyloxycarbamoyl)-3-methyl butylcarbamate
1
(4d): Oil; H NMR (CDCl3) ꢀ = 1.0 (d, 6H), 1.62 (dd, 2H), 1.83
(m, 1H), 4.3(dd, 1H), 4.08 (br s, 1H), 4.89 (s, 2H), 5.2 (s, 2H),
+
5.19 (br s, 1H), 7.33 - 7.38 (m, 10H); EIMS - 357 (M ); Anal.
Cald for C20H24N2O4: C, 67.40; H, 6.79; N, 7.86. Found: C,
67.39; H, 6.81; N, 7.89.

986
N. D. Kokare and D. B. Shinde
Vol 45
Nagawade, R. R.; Bahekar, S. S.; Shinde, D. B. Lett. in Org. Chem.
2005, 2, 398.
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