A facile and rapid preparation of hydroxamic acids by hydroxylaminolysis using DBU as base

Article abstract of DOI:10.1016/j.tetlet.2016.04.003

While there are many protocols for the preparation of hydroxamic acids from their corresponding carboxylic acid or carboxylic ester precursors, most use strong mineral bases that can lead to carboxylic acid impurities that can be difficult to remove using standard chromatographic techniques. This problem is exacerbated when the carbonyl group is hindered. Herein, we communicate a robust hydroxylaminolysis protocol for the preparation of hydroxamic acids in high yield and purity.

Full text of DOI:10.1016/j.tetlet.2016.04.003

Accepted Manuscript
A facile and rapid preparation of hydroxamic acids by hydroxylaminolysis using
DBU as base
Audrey Beillard, Yushma Bhurruth-Alcor, Claire Bouix-Peter, Karinne
Bouquet, Sandrine Chambon, Laurence Clary, Craig S. Harris, Corrine Millois,
Grégoire Mouis, Gilles Ouvry, Romain Pierre, Arnaud Reitz, Loic Tomas
PII:
S0040-4039(16)30344-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.003
TETL 47503
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 March 2016
31 March 2016
1 April 2016
Please cite this article as: Beillard, A., Bhurruth-Alcor, Y., Bouix-Peter, C., Bouquet, K., Chambon, S., Clary, L.,
Harris, C.S., Millois, C., Mouis, G., Ouvry, G., Pierre, R., Reitz, A., Tomas, L., A facile and rapid preparation of
hydroxamic acids by hydroxylaminolysis using DBU as base, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.04.003
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A facile and rapid preparation of
hydroxamic acids by hydroxylaminolysis
using DBU as base
Audrey Beillard, Yushma Bhurruth-Alcor, Karinne Bouquet, Claire Bouix-Peter, Sandrine Chambon, Laurence Clary,
Craig S. Harris, Corinne Millois, Grégoire Mouis, Gilles Ouvry, Romain Pierre, Arnaud Reitz, Loic Tomas

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
A facile and rapid preparation of hydroxamic acids by
hydroxylaminolysis using DBU as base
Audrey Beillard, Yushma Bhurruth-Alcor, Claire Bouix-Peter, Karinne Bouquet, Sandrine Chambon,
Laurence Clary, Craig S. Harris,* Corrine Millois, Grégoire Mouis, Gilles Ouvry, Romain Pierre, Arnaud
Reitz, Loic Tomas
Galderma R&D, 2400 Route de Colles, 06410 Biot, France
Abstract— While there are many protocols for the preparation of hydroxamic acids from their corresponding carboxylic acid or carboxylic
ester precursors, most use strong mineral bases that can lead to carboxylic acid impurities that can be difficult to remove using standard
chromatographic techniques. This problem is exacerbated when the carbonyl group is hindered. Herein, we communicate a robust
hydroxylaminolysis protocol for the preparation of hydroxamic acids in high yield and purity. © 2016 Elsevier Science. All rights reserved
———
* Craig Harris. Tel.: +33 (0)4 93 95 7042; fax: +33 (0)4 93 95 7071; e-mail: craig.harris@galderma.com
Keywords: hydroxylaminolysis, hydroxamic acid formation, DBU

2
Tetrahedron Letters
During a recent program, we became interested in preparing hydroxamic acids for an undisclosed target. The hydroxamic
acid group has consistently been used as a core binding group for the development of notably metalloenzyme inhibitors.1
While there are many protocols published to prepare hydroxamic acids either from the corresponding carboxylic acid
precursors in the presence of a suitable dehydrating agent and hydroxylamine or O-protected hydroxylamine derivatives,2-6 or
through direct hydroxylaminolysis from methyl ester substrates,7-10 we were disappointed by the overall ineffectiveness of
these processes when complex hindered carbonyl precursors (eg., 1 or 2) were employed for library synthesis (Table 1).
Table 1. A selection of the conditions screened for the preparation of 3.a Product distribution determined by LCMS.
Yield
(%)
% 1a
% 2a
% 3a
Entry
R
Conditions*
H
H
H
IBCF, NMM followed by NH2OH.HCl, DIPEA, 0 °C – r.t., 24 h
T3P, NH2OH.HCl, TEA, MeCN, 0 °C to r.t. , 24 h
Pfp-OH, EDCI, DMF followed by NH2OH.HCl, DIPEA, DMF,
r.t., 24 h
89
95
55
-
-
-
11
4
45
-
-
23
1
2
3
H
NBSoxy, DMAP, NH2OH.HCl, DIPEA, DMF, r.t., 24 h
7 eq NH2OH.HCl, KOH, MeOH, r.t., 24 h
7 eq NH2OH.HCl, NaOMe, MeOH, r.t., 24 h
10-50 eq NH2OH (50% aq), MeOH, r.t., 24 h
10 eq NH2OH (50% aq), MeOH, 60 °C, 24 h
20 eq NH2OH (50% aq), KCN, THF-MeOH, r.t., 72 h
10 eq NH2OH (50% aq), 3 eq DBU, MeOH, r.t., 48 h
10 eq NH2OH (50% aq), 3 eq DBU, MeOH, 40 °C, 16 h
10 eq NH2OH (50% aq), 3 eq DBU, MeOH, 60 °C, 16 h
65
35
45
1
78
12
30
45
70
-
35
43
45
0
19
20
19
-
-
-
59
-
-
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
22
10
99
20
76
0
2
12
70
49
30
9
10
11
12
6
0
* IBCF = isobutylchloroformate; T3P = propylphosphonic anhydride; NMM = N-methylmorpholine; DIPEA = N,N-diisopropylethylamine;
Pfp-OH = pentalfluorophenol; NBSoxy = ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate; DMAP = N,N-dimethylaminopyridine
Table 1 shows selected results from screening several conditions to form the desired hydroxamic acid product 3 from either
the carboxylic acid precursor 1 (entries 1-4) or the methyl ester precursor 2 (entries 5-12). In the case of the acid precursor 2,
only two sets of conditions (entries 3-4) afforded an acceptable conversion to 3 albeit with poor overall isolated yields. Direct
hydroxylaminolysis of the methyl ester precursor (entries 5-6) using “dry hydroxylamine” afforded a reasonable conversion
towards the hydroxamic acid product 3 but with an almost equal quantity of the carboxylic acid impurity 1 that was difficult
to remove by chromatography. Attempts to obtain a complete reaction by using a large excess of hydroxylamine in the
absence of a strong base failed at room temperature and heating the reaction mixture afforded practically only the carboxylic
acid impurity 1 (entries 7 & 8). From previous experience in the team, we found that the addition of KCN as the catalyst, as
disclosed by Cho and co-workers at Merck’s Laboratories,9 did dramatically increase the ratio of hydroxamic acid product
over carboxylic acid impurity in the case of non-hindered esters (eg., entry 4, condition C, Table 2). However, application of
these conditions to the more hindered precursor 2 afforded little conversion (entry 9). Attempts to increase the conversion by
heating or adding more KCN only increased the level of carboxylic acid impurity. Finally, we postulated that employment of
a nucleophilic superbase11 such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)12 could be an interesting alternative to strong
mineral bases such, as KOH or NaOMe, in order to reduce in situ saponification of the ester during the reaction. To our
delight, the reaction proceeded very smoothly affording the final compound in acceptable isolated yield after chromatography
(entry 10). Attempts to decrease reaction times by heating the reaction mixture only led to poorer conversions to the desired
hydroxamic acid product and an increase in the carboxylic acid impurity (entries 11, 12).

Tetrahedron Letters
3
With this knowledge in hand, we decided to retain DBU as the base and evaluate the scope of the reaction conditions with
other ester substrates. In certain cases, these conditions were compared to conditions previously used by the team during this
research programme to determine what influence they had on product distribution with respect to structural variation (Table
2).
Table 2. A selection of comparative results using the DBU process. Conditions A: NH2OH (50% aq) (10 eq), DBU (3 eq), MeOH (4 vol),
r.t.; conditions B: NH2OH (50% aq) (10 eq), MeOH (4 vol), r.t.; conditions C: NH2OH (50% aq) (20 eq), KCN (5 mol%), MeOH-THF
(1:1, 10 vol), r.t.
Carboxylic
acid (%)a
Hydroxamic
acid (%)a
Ester (%)a
Isolated yield (%)b
Entry
Substrate
Conditions
Time
A
48 h
30
0
70
59
1
A
A
12 h
5
2
0
0
95
98
76
77
2
3
2 h
A
B
20 min.
24 h
1
3
0
99
15
82
-
82
4
5
C
A
24 h
72 h
4
0
0
96
68
78
47
32
C
96 h
4
95
1
-

4
Tetrahedron Letters
A
30 min
0
1
99
82
6
7
A
C
24 h
96 h
10
15
0
90
12
75
-
75
A
A
1 h
1
0
0
99
76
81
61
8
9
32 h
24
A
B
5 min
1 h
3
5
0
0
97
95
76
-
10
A
B
15 min
3 h
5
9
0
0
95
91
-
-
11
12
A
B
6 h
6 h
2
4
0
98
13
-
-
83
A
A
A
3 h
5 h
1 h
5
5
1
0
95
0
95
-
-
-
13
14
15
99
91

Tetrahedron Letters
5
A
A
1 h
1 h
10
4
0
0
90
96
54
64
16
17
86
A
1 h
3
0
97
18
(e.r. = >99:1)
Table 2 shows the results of a small library of hydroxamic acids prepared using this process in order to give the reader an
idea of substrate scope. It is clear that steric hindrance affects the ratio hydroxamic acid to carboxylic acid whereby yields of
hydroxamic acid product increased on reducing the ring size and reaction times reduced dramatically (entries 1-3 & 7-8).
Decreasing further steric hindrance by adding an additional methylene group between the core and the ester group (entry 3 vs
4 & 6) decreased reactions times down from 4 hours to a remarkable 30 minutes with a ratio of hydroxamic acid / carboxylic
acid of >99:1. We also compared the conditions head-to-head with the KCN catalyzed process (entry 4 & entry 5) and found
not only was the reaction much faster (20 min. compared to 24 h) but there was a cleaner crude reaction profile with <1% of
carboxylic acid impurity. As a control reaction, we carried out the reaction in the absence of a catalyst and observed very
little conversion (entry 4, condition B). Increased hindrance around the methyl ester moiety led to more carboxylic acid
(entry 4 v entry 5). Next we turned our attention to more reactive benzoate esters (entries 10-14). In general, the effect of
adding DBU became dominant where the carbonyl was the most sterically congested. In all cases where DBU was present,
the reaction was much faster than in the absence of DBU (entries 10-13) and even i-Pr esters were efficiently converted to
hydroxamic acids in high purity where the control reaction failed (entry 12). As expected, no reaction took place using tert-
butyl esters (entry 14) as substrates. These conditions were also efficient in the presence of other electrophilic functionality
(entries 15-17) whereby unsaturated esters and heteroaromatic substrates gave excellent conversions to hydroxamic acid
products. Finally, we also show that no erosion of the chiral center was observed when using L-phenyl alanine methyl ester as
a model substrate under these conditions (entry 18).
Scheme 1. Application of PS-DBU for the formation of hydroxamic acids
Finally, we successfully evaluated the effects of employing immobilized DBU (PS-DBU) in this process with the aim of
developing a process that would afford hydroxamic acid products without the need for chromatography. As expected, the
reaction rates were greatly compromised whereby complete conversion to hydroxamic acid products required 16 h compared
to 1 h using free DBU using unhindered esters as the substrates (Table 3, entry 1 v 2). Base washing with methanolic
ammonia was also necessary to regenerate the polymer supported DBU free base for successive use without comprising
reaction rates (entry 3 v 4 and 5). Unfortunately, the conditions were impractical when hindered ester substrates were
employed (eg., entry 6 v 7) that we believe is due to the poor swelling of the polystyrene support in the polar medium.
Table 3. Application of PS-DBU for this hydroxylaminolysis process. N/A = not analysed

6
Tetrahedron Letters
Conversion
(%)
Enantiomeric
ratio
Entry
1
Substrate
Conditions
Time
DBU (3 eq), 50% NH2OH (aq) (10 eq),
MeOH (4 vol)
1 h
97
95
65
96
93
99:1
99:1
N/A
99:1
99:1
Cycle 1: PS-DBU, 50% NH2OH (aq)
(10 eq), DCM-MeOH (1:1, 4 vol)
16 h
16 h
16 h
16 h
2
3
4
5
Cycle 2: Un-treated PS-DBU, 50%
NH2OH (aq) (10 eq), DCM-MeOH
(1:1, 4 vol)
Cycle 2: Pre-treatment of PS-DBU
(NH3/MeOH 7N) , 50% NH2OH (aq)
(10 eq), DCM-MeOH (1:1, 4 vol)
After 5 cycles of pre-treatment of PS-
DBU (NH3/MeOH 7N) , 50% NH2OH
(aq) (10 eq), DCM-MeOH (1:1, 4 vol)
PS-DBU, 50% NH2OH (aq) (10 eq),
DCM-MeOH (1:1, 4 vol)
16 h
99
-
-
6
7
PS-DBU, 50% NH2OH (aq) (10 eq),
DCM-MeOH (1:1, 4 vol)
16 h
8
In conclusion, we have discovered a very efficient and robust hydroxylaminolysis process, using both DBU in solution and
immobilized on a solid support, to prepare libraries of hydroxamic acids and demonstrated its potential on a wide range of
complex ester substrates with good to excellent results. Work is ongoing to further optimise the reaction conditions.14
Acknowledgements
The authors would like to acknowledge Spirochem AG for supplying a selection of the starting materials to prepare the
substrates cited in the tables.

Tetrahedron Letters
7
Supplementary data
Full experimental procedures and supporting LCMS, 1H- and13C-NMR characterisation data are available for a selection of
compounds described in this letter is available at no extra charge via the on-line version.
References and notes
1. a) Muri, E. M. F.; Nieto, M.J.; Sindelar, R. D.; Williamson, J. S. Curr. Med. Chem. 2002, 9, 1631-1653; b)
Kontogiorgis, C. A.; Papaioannou, P.; Hadjipavlou-Litina, D. J. Curr. Med. Chem. 2005, 12, 339-355.
2. Lombart, H.-G.; Feyfant, E.; Joseph-McCarthy, D.; Huang, A.; Lovering, F.; Sun, Lin H.; Zhu, Y.; Zeng, C.; Zhang,
Y.; Levin, J. Bioorg. Med. Chem. Lett. 2007 17, 4333-4337.
3. Vasanthaa, B.; Hemantha, H. P. ; Sureshbabu, V. V. Synthesis 2010, 2990-2996.
4. Brookings, D. C.; Davis, J. M.; Langham, B. J. PCT Int. Appl., 2004000846.
5. Krchnak, V. Mini-Rev. Med. Chem. 2006, 6, 27-36.
6. Kishore T.; Srinivasa R. M.; Dharm D., Bhubaneswar M. J. Org. Chem. 2014, 79, 3765–3775 and referenced cited
therein.
7. Duan, J.; King, B. W.; Decicco, C.; Maduskuie, T. P.; Voss, M. E; Gilmore, J. L.; King, B. W.; Harris, C.;
Maduskuie, T.; Mercer, S. E.; Liu, R-Q.; Covington, M. B.; Qian, M.; Ribadeneria, M. D.; Vaddi, K.; Trzaskos, J.
M.; Newton, R. C.; Decicco, C. P.; Duan, J. Bioorg. Med. Chem. Lett. 2006, 16, 2699-2704.
8. Levin, J. I.; Chen, J. M.; Cole, D. C.; Du, M. T.; Laakso, L. M. 2001, US 622531.
9. Ho, C.Y.; Strobel, E.; Ralbovsky, J.; Galemmo, R. A. Jr. J. Org. Chem. 2005, 70, 4873–4875.
10. Gediya, L.K.; Chopra, P.; Purushottamachar, P.; Maheshwari, N.; Njar, V.C. J. Med. Chem. 2005, 48, 5047-5051.
11. a) Ishikawa, T.; Harwood L. M. Synlett 2013, 24, 2507-2509; b) Ishikawa, T. Superbases for Organic Chemistry
2009, John Wiley & Sons; c) Leito, I.; Koppel, I. A.; Koppel, I.; Kaupmees, K.; Tshepelevitsh, S.; Saame, J. Angew.
Chem. Int. Ed. 2015, 54, 9262 –9265.
12. For recent references showing DBU as a nucleophilic catalyst, please consult: a) Shieh,W-C; Dell, S; Repič, O. J.
Org. Chem. 2002, 67, 2188–2191; b) Horn, H. W.; Jones G. O.; Wei, D. S.; Fukushima, K.; Lecuyer, J. M.; Coady,
Daniel J.; Hedrick, J. L.; Rice, J. E. J. Phys. Chem. A 2012, 116, 12389–12398.
13. Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401–3430.
14. Typical procedure: To a stirred solution of the methyl ester (1 eq) in MeOH (4 volumes), was added DBU (3 eq) and
50% v/v aqueous solution NH2OH (aq) (10 eq) at 0 °C to room temperature. The reaction mixture was stirred for 20
minutes to 48 h (depending on the steric hindrance around the ester) and then purified directly by mass-triggered
preparative LCMS Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length,
flow rate of 40 ml / minute) and decreasingly polar mixtures of water (containing 0.1% formic acid) and acetonitrile
as eluent. The fractions containing the desired compound were evaporated to dryness to afford the final compounds
usually as a crystalline solid.

8
Tetrahedron Letters
An efficient process to prepare hindered




hydroxamic acids from esters is proposed.
Quickest reaction times and best yields were
observed when using DBU as the base.
A
chromatography-free process using
recyclable PS-DBU is also disclosed.
No epimerisation occured when using L-
phenylalanine methyl ester as the substrate.