Design, synthesis and utilization of a novel coupling reagent for the preparation of O-alkyl hydroxamic acids

Article abstract of DOI:10.1016/j.tetlet.2007.04.058

An efficient novel reagent, phosphoric acid diethyl ester 2-phenyl-benzimidazol-1-yl ester, was designed, and synthesized and its applicability was demonstrated for the preparation of O-alkyl hydroxamic acids. The O-alkyl hydroxamic acids of N-protected a

Full text of DOI:10.1016/j.tetlet.2007.04.058

Tetrahedron Letters 48 (2007) 4437–4440
Design, synthesis and utilization of a novel coupling reagent
for the preparation of O-alkyl hydroxamic acids
Nagnnath D. Kokare,a,b Rahul R. Nagawade,a,b Vipul P. Ranea,b and
Devanand B. Shindea,*
aDepartment of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, MS, India
bWockhardt Research Centre, Aurangabad 431 210, MS, India
Received 9 January 2007; revised 2 April 2007; accepted 13 April 2007
Available online 19 April 2007
Abstract—An efficient novel reagent, phosphoric acid diethyl ester 2-phenyl-benzimidazol-1-yl ester, was designed, and synthesized
and its applicability was demonstrated for the preparation of O-alkyl hydroxamic acids. The O-alkyl hydroxamic acids of N-pro-
tected amino acids were also synthesized. The enantiomeric purity of the synthesized compounds were measured using chiral HPLC
and the degree of racemization was found to be negligible.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
preparation of a salt of hydroxylamine followed by
addition of the ester in alcohol as solvent8 or activation
of the acid by reaction with an acyl chloride or mixed
anhydride and quenching with O-protected hydroxyl-
amine analogues.9 Although some of these methods
are quite efficient for the preparation of substituted
hydroxamic acids, there are drawbacks such as instabil-
ity, toxicity, high volatility of some acylating agents,
high cost and difficult purification which limit their
applications. Thus, the development of a convenient
method is important for the efficient preparation of
hydroxamic acids from carboxylic acids. We have there-
fore designed and synthesized a novel reagent and dem-
onstrated its applicability for the efficient preparation of
hydroxamic acids.
Hydroxamic acids are important components of many
chemotherapeutic agents such as the succinate-based
matrix metalloproteinase (MMP) inhibitors,1 class I/II
histone deacetylase (HDAC) inhibitors2 and iron-con-
taining antibiotics.3 Also, hydroxamic acid analogues
are important targets for the medicinal chemist because
of the intrinsic chelating properties of this functional
group with Zn++ at the active site of metalloproteins.4,5
Recently, various methods have been reported for the
preparation of hydroxamic acids starting from carb-
oxylic acids or their derivatives6 and N-acyloxazolidi-
nones.7 The solution-phase hydroxyamination of esters
is generally achieved via a two-step sequence; firstly,
N
c
NO2
NH2
b
N
N
a
N
N
OH
N
O
O
O
P
Bn
OEt
EtO
1
2
3
4
Scheme 1. Synthesis of reagent 4. Reagents and conditions: (a) NaH, BnBr, THF, 80 ꢁC, 4 h; (b) 10% Pd/C, H2, methanol, 15 min; (c) (EtO)2P(O)Cl,
Et3N, dichloromethane, 30 min, 0 ꢁC.
Keywords: Hydroxamic acid; N-Hydroxy-2-phenylbenzimidazole; O-Benzyl hydroxylamine; Amino acids.
*
Corresponding author. Tel.: +91 9822608745; e-mail: dbschemtech@hotmail.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.058

4438
N. D. Kokare et al. / Tetrahedron Letters 48 (2007) 4437–4440
N-Hydroxy-2-phenylbenzimidazole 3 was synthesized
according to the reported procedure10 which involves
the reaction of o-nitroaniline with benzyl bromide using
sodium hydride as base, followed by benzyl deprotection
using 10% Pd/C to give the desired product as a white
crystalline solid. The coupling reagent 4 was synthesized
by treating 3 with diethyl chlorophosphate and triethyl-
amine in dichloromethane. The reagent was isolated as a
Table 1. Synthesis of different O-alkyl hydroxamic acids using reagent 4
O
O
4
O
O
R1
N
R2
H2N
R2
+
R1
Product
OH
H
Entry
R1
R2
Bn
Reaction time (min)
Yield (%)
Mp ꢁC
Found
Reported
O
102–10411
O
1
45
96
101–102
50–51
N
H
O
O
5013
O
O
2
Allyl
40
94
N
H
3
4
Et
45
35
91
93
82–83
81–8214
N
H
O
O
O
13611
O
O
O
Bn
134–135
N
H
Br
Cl
Br
5
6
7
Bn
Bn
Bn
40
35
45
97
96
95
157–158
140–141
108–109
15813
N
H
Cl
Cl
Cl
14213
N
H
Cl
Cl
O
110–11111
O
N
H
MeO
MeO
O
O
8
9
Bn
Bn
Bn
Bn
Bn
50
25
50
40
35
91
99
93
89
92
125–126
166–167
98–99
12813
N
H
H3C
O2N
H3C
O2N
O
O
166–16711
99–10011
72–7311
99–10111
N
H
O
O
10
11
12
N
H
O
O
71–72
N
H
N
N
O
O
98–99
O
N
O
H

N. D. Kokare et al. / Tetrahedron Letters 48 (2007) 4437–4440
4439
Table 2. Synthesis of different O-benzyl hydroxamic acids from N-
protected amino acids using reagent 4
white crystalline solid and used for coupling several car-
boxylic acids with various O-alkyl hydroxylamines
(Scheme 1).
Entry Product
Yielda (%) eeb (%)
O
Initially we studied the synthesis of N-hydroxybenz-
amide from benzoic acid and hydroxylamine hydrochlo-
ride, but all variations of solvent, temperature, base and
equivalents were unsuccessful. N-Benzyloxybenzamide
was isolated in 96% yield using 3.5 equiv of DIPEA in
DMF. To improve the yield and minimize the problems
in large-scale synthesis, a method was developed in
which reagent 4 could be synthesized from 3 and used
in situ for the synthesis of O-alkyl hydroxamic acids.
An easy work-up is an advantage of this method, requir-
ing only acid–base treatment and trituration with a
suitable solvent to give sufficiently pure product. Also
during the work-up, N-hydroxy-2-phenylbenzimidazole
could be easily isolated by acid–base treatment and
could be reused for the synthesis of reagent 4.
H
1
89
92
68
98.3
96.8
94.1
N
O
Boc
N
H
O
H
N
2
3
O
Cbz
Boc
N
H
O
O
H
N
O
O
N
H
H
N
4
5
74
91
95.2
95.8
Cbz
N
H
Boc
O
Using similar reaction conditions, 12 different O-alkyl
hydroxamic acids were synthesized and the results
obtained are summarized in Table 1. All the synthesized
hydroxamic acids were characterized by mass, IR
and 1H NMR measurements. Acids with electron-
withdrawing substituents (e.g., nitro, entry 9) required
a comparatively shorter reaction time than acids with
electron-donating groups (e.g., methyl, entry 8) or those
without substituents (entries 2 and 3). Compound 4
shows superiority over existing reagents regarding both
yields and purification. In particular, 4-nitro-N-benzyl-
oxybenzamide (entry 9) was isolated in higher yield
(99%) than previously reported (37%).11
N
O
N
H
O
H
N
O
Cbz
N
6
7
87
76
96.7
94.6
H
O
O
O
N
H
O
a Isolated yield.
b Enantiomeric excess determined by chiral HPLC.
O-Benzylhydroxylamine was also coupled with N-pro-
tected amino acids (Table 2). For these reactions, mod-
erate to good yields were obtained in the range 68–92%.
The extent of racemization was measured using chiral
HPLC. The enantiomeric excess obtained was in the
range 94.1–98.3%, which proves the efficiency of cou-
pling reagent 4 for optically active substrates.
The advantages of this coupling reagent are its scalabil-
ity, and high yields of products. Also, for the preparation
of O-benzyl-protected hydroxamic acids from amino
acids, the observed racemization was minimal.
The optical rotations of some of the synthesized
compounds were measured and compared with the
corresponding reported values. In the case of (1-benzyl-
oxycarbamoyl-ethyl)carbamic acid tert-butyl ester
(entry 1), the reported specific rotation was [a]D À58.3
(c 0.1, CHCl3)12 whilst that for our product was [a]D
À58.1 (c 0.1, CHCl3). For 2,2,5-trimethyl-[1,3]-dioxo-
lane-4-carboxylic acid benzyloxy amide (entry 7), the re-
ported specific rotation was [a]D 25.6 (c 1.1, MeOH)13
and we obtained [a]D 25.9 (c 1.1, MeOH).
2. Preparation of phosphoric acid diethyl ester
2-phenylbenzimidazol-1-yl ester 4
A solution of N-hydroxy-2-phenylbenzimidazole (0.42 g,
0.02 mol) and triethylamine (0.7 ml, 0.05 mol) was stir-
red in DCM (2.5 ml) and diethyl chlorophosphate
(0.21 ml, 0.024 mol) was added at 0 ꢁC. The reaction
mixture was stirred until completion of the reaction
(TLC). Then, the 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 extracts were concentrated to give
the title compound 4 as a white solid.
Intermediate 5 formed from the reaction of benzoic acid
and O-benzylhydroxylamine was isolated and character-
1
ized by mass spectrometry and H NMR spectroscopy.
We suggest that firstly benzoic acid reacts with 4 to give
the active ester 5 and this then reacts with O-benzylhydr-
oxylamine (Scheme 2).
Yield—462 mg, (67%); mp 112–116 ꢁC (dec); IR (Nujol,
cmÀ1) 2985, 1298, 1036, 981; 1H NMR (CDCl3,
400 MHz) d 1.2 (t, J = 6.2 Hz, 6H), 4.1 (q, J = 7.4 Hz,
4H), 7.3 (m, 3H), 7.5 (d, J = 8.1 Hz, 2H), 7.8 (d,
J = 8.3 Hz, 2H), 8.2 (d, J = 8.3 Hz, 2H); EIMS
m/z = 347 (M+H)+; Anal. Calcd for C17H19N2O4P: C,
58.96; H, 5.53; N, 8.06. Found: C, 59.23; H, 5.61; N, 8.11.
In conclusion, reagent 4 was easily synthesized from
cheap starting materials and used in situ for the prepara-
tion of O-alkyl hydroxamic acids from carboxylic acids.

4440
N. D. Kokare et al. / Tetrahedron Letters 48 (2007) 4437–4440
O
O
O
N
N
BnONH2
4
+
OH
N
O
O
N
N
H
OH
5
Scheme 2. Isolation of intermediate 5.
Belvedere, S. J. Med. Chem. 2003, 46, 5097–5116; (c) Kim,
D. K.; Lee, J. Y.; Kim, J. S.; Ryu, J. H.; Choi, J. Y.; Lee,
J. W.; Kim, T. K.; Seo, J. W.; Park, H. J.; Yoo, J.; Park, J.
H.; Kim, T. U.; Bang, Y. J. Med. Chem. 2003, 46, 5745–
5754; (d) Lu, Q.; Yang, Y.-T.; Chen, C.-S.; Davis, M.;
Byrd, J. C.; Etherton, M. R. J. Med. Chem. 2004, 47, 467–
474.
3. General procedure for synthesis O-alkyl
hydroxamic acids
A
solution of N-hydroxy-2-phenylbenzimidazole
(0.02 mol) and DIPEA (0.07 mol) was stirred in DMF
and diethyl chlorophosphate (0.024 mol) was added
with cooling. The reaction mixture was stirred for
10 min and carboxylic acid (0.016 mol) was added and
the mixture was stirred for a further 10 min at 0 ꢁC for
active ester formation. Then, O-alkyl hydroxylamine
(0.03 mol) was added and the mixture stirred at room
temperature until completion of the reaction (TLC).
Saturated aq NaCl (20 ml) solution was then 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 with
water (2 · 20 ml). The organic layer was dried over so-
dium sulfate, filtered and evaporated to give the corre-
sponding O-alkyl hydroxamic acid.
3. (a) Miller, M. J. Chem. Rev. 1989, 89, 1563–1662; (b)
Bergeron, R. J.; Wiegand, J.; McManis, J. S.; Perumal, P.
T. J. Med. Chem. 1991, 34, 3182–3188.
4. Jung, M. Curr. Med. Chem. 2001, 8, 15065–15071.
5. Brown, P. D.; Davidson, A. H.; Gearing, A.; Whittakar,
M. Hydroxamic acid matrix metalloproteinase inhibitors.
In Matrix Metalloproteinase Inhibitors in Cancer Chemo-
therapy; Clendeninn, N. J., Appelt, K., Eds.; Humana
Press: Totowa, NJ, 2001, pp 113–142.
6. (a) Koshiti, N.; Reddy, G. V.; Jacobs, H.; Gopalan, A.
Synth. Commun. 2002, 32, 3779–3790; (b) Bailen, M. A.;
Chinchilla, R.; Dodsworth, D. J.; Najera, C. Tetrahedron
Lett. 2001, 42, 5013–5016; (c) Fray, M. J.; Burslm, M. F.;
Dickenson, R. P. Bioorg. Med. Chem. Lett. 2001, 11, 567–
570; (d) Dankwardt, S. M.; Billedeau, R. J.; Lawley, L. K.;
Abbot, S. C.; Martin, R. L.; Chan, C. S.; Van Wart, H. E.;
Walker, K. A. M. Bioorg. Med. Chem. Lett. 2000, 10,
2513–2516; (e) Nikam, S. S.; Kronberg, B. E.; Johnson, D.
R.; Doherty, A. M. Tetrahedron Lett. 1995, 36, 197–200;
(f) Altenburger, J. M.; Mioskowski, C.; d’Orchymont, H.;
Schirlin, D.; Schalk, C.; Tarnus, C. Tetrahedron Lett.
1992, 33, 5055–5058; (g) Barlaam, B.; Harmon, A.;
Maudet, M. Tetrahedron Lett. 1998, 39, 7865–7868; (h)
Ando, W.; Tsumaki, H. Synth. Commun. 1983, 13, 1053–
1056; (i) King, F. D.; Pike, S.; Walton, D. R. M. J. Chem.
Soc., Chem. Commun. 1978, 351–356.
4. N-Benzyloxy-4-nitrobenzamide
Mp 166–167 ꢁC (dec); IR (Nujol, cmÀ1) 3196, 2932,
1671, 1524; 1H NMR (CDCl3, 400 MHz) d 5.03 (s,
2H), 7.36–7.48 (m, 5H), 7.9 (d, J = 8.4 Hz, 2H), 8.2 (d,
J = 8.4 Hz, 2H); EIMS m/z—273 (M+H)+; Anal. Calcd
for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C,
61.92; H, 4.57; N, 10.13.
7. Sibi, M. P.; Hasegawa, H.; Ghorphade, S. R. Org. Lett.
2002, 4, 3343–3346.
Acknowledgement
8. Hauser, C. R.; Renfrow, W. B. In Organic Synthesis;
Wiley: New York, 1943; Collect Vol. II, pp 67–68.
9. (a) Burns, C. J.; Groneberg, R. D.; Salvino, J. M.;
McGeehan, G.; Condon, S. M.; Morris, R.; Morrissette,
M.; Mathew, R.; Darnbrough, S.; Neuenschwander, K.;
Scotese, A.; Djuric, S.; Ullrich, J.; Labaudiniere, R.
Angew. Chem., Int. Ed. 1998, 37, 2848–2850; (b) Mori,
K.; Koseki, K. Tetrahedron 1988, 44, 6013–6020.
10. Gardiner, J. M.; Procter, J. Tetrahedron Lett. 2001, 42,
5109–5111.
The authors are thankful to the Head, Department of
Chemical Technology, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad 431004 (MS), In-
dia for providing the laboratory facilities.
References and notes
11. Arnaud, G.; Alessandro, V.; Matteo, Z. J. Org. Chem.
2005, 70, 6925–6928.
12. Ramasamy, K.; Olsen, R. K.; Emery, T. J. Org. Chem.
1981, 46, 5438–5441.
13. Jeum-Jong, J.; Young-Dae, P.; Ho-Kyun, K.; Su-dong, C.;
Ju-Kyeon, K. Synth. Commun. 2005, 35, 731–738.
14. Alan, R. K.; Nataliya, K.; Boris, V. R. Synthesis 2003,
2777–2780.
1. For a review see: (a) Whittaker, M.; Floyd, C. D.; Brown,
P.; Gearing, A. J. H. Chem. Rev. 1999, 99, 2735–2776; (b)
Caldarrelli, M.; Habermann, J.; Ley, S. V. Bioorg. Med.
Chem. Lett. 1999, 9, 2049–2054.
2. (a) Finnin, M. S.; Doniggain, J. R.; Cohen, A.; Richon, V.
M.; Rifkind, P. A. Marks; Breslow, R.; Pavletich, N. P.
Nature 1999, 401, 188–193; (b) Miller, T. A.; Witter, D. J.;