Convenient preparation of O-linked polymer-bound N-substituted hydroxylamines, intermediates for synthesis of N-substituted hydroxamic acids

Article abstract of DOI:10.1021/ol006152g

An efficient procedure for preparation of O-linked polymer-bound N-substituted hydroxylamines by reduction of resin-bound oximes with borane·pyridine complex in the presence of dichloroacetic acid is reported. Other reducing systems commonly used for imine or oxime reduction were ineffective, including borane·pyridine in the presence of acetic acid. Oximes derived from a variety of aromatic and aliphatic aldehydes and ketones were successfully reduced. The N-substituted products were acylated and cleaved from resin to afford N-substituted hydroxamic acids.

Full text of DOI:10.1021/ol006152g

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2777-2779
Convenient Preparation of O-Linked
Polymer-Bound N-Substituted
Hydroxylamines, Intermediates for
Synthesis of N-Substituted Hydroxamic
Acids
Dale E. Robinson and Mark W. Holladay*
SIDDCO, Inc., 9040 S. Rita Road, Suite 2338, Tucson, Arizona 85747
holladay@siddco.com
Received June 2, 2000
ABSTRACT
An efficient procedure for preparation of O-linked polymer-bound N-substituted hydroxylamines by reduction of resin-bound oximes with
borane‚pyridine complex in the presence of dichloroacetic acid is reported. Other reducing systems commonly used for imine or oxime
reduction were ineffective, including borane‚pyridine in the presence of acetic acid. Oximes derived from a variety of aromatic and aliphatic
aldehydes and ketones were successfully reduced. The N-substituted products were acylated and cleaved from resin to afford N-substituted
hydroxamic acids.
Hydroxamic acids are of interest as inhibitors of metallo-
proteases,1 and solid-phase methods offer an attractive
general approach to this class of compounds.2 N-Substituted
hydroxamic acids also are of interest in the same context,
and combinatorial solid-phase synthesis of such compounds
has recently been reported.3 In addition, polymer-bound
N-benzylic hydroxamic acids have been utilized as key
intermediates for convenient preparation of aldehydes.4 The
route shown in Scheme 1, whereby an O-linked polymer-
bound alkoxylamine 12a-c,e,i is treated with an aldehyde or
ketone to form the corresponding oxime, followed by oxime
reduction and acylation, would appear to be a straightforward
approach to solid-phase synthesis of N-substituted hydrox-
amic acids. However, reported attempts to reduce this
strategy to practice have been unsuccessful owing to an
inability to cleanly reduce O-linked resin-bound oximes 2
to the corresponding N-substituted hydroxylamine derivatives
3 using a variety of conditions (NaBH3CN in HOAc/MeOH/
THF; NaBH(OAc)3; NaBH4; LiBHEt3).3,4 Accordingly, pre-
vious workers have resorted to N-alkylation of N-urethane-
protected alkoxylamine derivatives using primary or activated
alkyl halides, either prior to or after attachment to the solid
phase. In this report, we describe our successful efforts to
achieve clean reduction of 2 to 3, which can be followed by
acylation and cleavage from the resin to provide N-substituted
(1) Hagmann, W. K.; Lark, M. W.; Becker, J. W. Ann. Rep. Med. Chem.
1996, 32, 231-240.
(2) (a) Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M. Tetrahedron
Lett. 1996, 37, 8045-8048. (b) Richter, L. S.; Desai, M. C. Tetrahedron
Lett.1997, 38, 321-322. (c) Mellor, S. L.; McGuire, C.; Chan, W. C.
Tetrahedron Lett. 1997, 38, 3311-3314. (d) Ngu, K.; Patel, D. V. J. Org.
Chem. 1997, 62, 7088-7089. (e) Bauer, U.; Ho, W.-B.; Koskinen, A. M.
P. Tetrahedron Lett. 1997, 38, 7233-7236. (f) Khan, S. I.; Grinstaff, M.
W. Tetrahedron Lett. 1998, 39, 8031-8034. (g) Dankwardt, S. M. Synth.
Lett. 1998, 761. (h) Zhang, Y.; Li, D.; Houtman, J. C.; Witiak, D. T.; Seltzer,
J.; Bertics, P. J.; Lauhon, C. T. Bioorg. Med. Chem. Lett. 1999, 9, 2823-
2826. (i) Barlaam, B.; Koza, P.; Berriot, J. Tetrahedron 1999, 55, 7221-
7232.
(3) Mellor, S. L.; Chan, W. C. J. Chem. Soc., Chem. Commun. 1997,
2005-2006.
(4) Salvino, J. M.; Mervic, M.; Mason, H. J.; Kiesow, T.; Teager, D.;
Airey, J.; Labaudiniere, R. J. Org. Chem. 1999, 64, 1823-1830.
10.1021/ol006152g CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

Scheme 1. Solid-Phase Synthesis of N-Substituted
Table 1. Results for Attempted Reductions of Oxime 2a
Hydroxamic Acids
entry
conditionsa
resultsb,c
1
2
NaCNBH3 (10), 1:1 HOAc/DMF min oxime reduction
NaBH(OAc)3 (10), HOAc (10),
DMF/CH2Cl2
min oxime reduction
min oxime reduction
min oxime reduction
min oxime reduction
min oxime reduction
partial oxime reduction
3
4
Me4NBH(OAc)3 (5),
1:1:1 HOAc/CH3CN/CH2Cl2
Ph2SiH2 (3), Ti(OiPr)4 (3),
H2Cl2
5
Me2PhSiH (3), TCA (3),
CH2Cl2
6
BH3‚pyridine (10), HOAc (10),
CH2Cl2
7
BH3‚pyridine (3), TCA (18),
CH2Cl2
8
BH3‚pyridine (10), TCA (15),
CH2Cl2
BH3‚pyridine (10), TFA (15),
CH2Cl2
BH3‚pyridine (10), DCA (15),
CH2Cl2
BH3‚pyridine (5), DCA (7.5),
CH2Cl2
5a (93%),
no N-O cleavage
5a (89%),
9
N-O cleavage (8%)
5a (97%),
10
11
12
13
14
no N-O cleavage
5a (97%),
no N-O cleavage
unreacted oxime (97%)
BH3‚pyridine (10), CA (15),
CH2Cl2
BH3‚THF (1.1), THF
hydroxamic acids. This approach offers access to hydroxamic
acids having a broad range of nitrogen substituents and
complements existing methods that utilize alkyl halides as
synthons for substituents at this position.
2a (61%), 5a (24%),
N-O cleavage (15%)
5a (87%),
NaCNBH3 (10), 1:1 DCA/DMF
no N-O cleavage
We chose Wang resin as the solid support for these studies,
owing primarily to its commercial availability with high
loading levels.5 Initial efforts were focused on investigating
conditions for reduction of oxime 2a, which was formed by
treatment of the known2a Wang resin bound hydroxylamine
1a with excess benzaldehyde in the presence of trimethyl
orthoformate (TMOF) in THF. The results from treatment
of 2a under a variety of reducing conditions are shown in
Table 1 and support and complement previous observations
that many of the common conditions for imine or oxime
reduction work poorly in this system. Conditions reported
by Kawase and Kikugawa6 utilizing BH3‚pyridine in the
presence of HCl appeared promising for the reduction of
O-alkyloximes, but the solvents used (water, ethanol) are
poorly compatible with polystyrene resin, and acid lability
of the resin linkage must be considered. Therefore, BH3‚
pyridine in the presence of weaker acids using dichlo-
romethane as the solvent was investigated. Although BH3‚
pyridine in the presence of acetic acid7 failed to effect
reduction (entry 1), BH3‚pyridine in the presence of trichlo-
roacetic acid (TCA) resulted in partial (entry 7) or essentially
complete (entry 8) conversion to the desired product,
depending on the number of equivalents of reducing agent
used. In the experiments represented by entries 8-14, it
proved beneficial for analytical purposes to subject the
product mixture to benzoylation conditions (∼10 equiv
a Reactions were conducted at room temperature for 16-18 h. Numbers
in parentheses indicate number of equivalents of reagent relative to oxime
substrate. Abbreviations: CA, DCA, TCA: mono-, di-, and trichloroacetic
acids, respectively; TFA, trifluoroacetic acid. b Entries 8-14 represent
experiments that were carried through the entire sequence in Scheme 1 (a
series). Extent of N-O cleavage was inferred from the amount of benzoic
acid produced. c Values expressed as percentages refer to relative peak area
in the HPLC of the crude reaction mixture, monitored at 215 nm. Peak
identities were supported by LC/MS.
PhCOCl, NEtiPr2, CH2Cl2, 4-DMAP) prior to cleavage (1:1
TFA/CH2Cl2). Under these conditions, the desired product
is converted to hydroxamate 5a, which contains a better
chromophore than the unbenzoylated product for detection
by HPLC/UV. Moreover, reductive cleavage of the N-O
bond is potentially a side reaction in the reduction of oximes
to hydroxylamine derivatives, and benzoylation permits
detection of the extent of this side reaction by ultimately
producing benzoic acid. Entries 9 and 13 demonstrate that
over-reduction can indeed be an issue in the present system,
i.e., BH3‚pyridine in the presence of trifluoroacetic acid8
caused some over-reduction, and BH3‚THF, even when used
in only slight excess, resulted both in over-reduction and
unreacted oxime.
The results of experiments designed to investigate the
effect of small changes in the successful BH3‚pyridine/TCA/
CH2Cl2 system described above also are included in Table
1. Dichloroacetic acid (DCA) in place of TCA also gave
(5) Wang resin with nominal loading of 1.4 mmol/g was purchased from
Chem Impex Internation, Inc., Wood Dale, IL.
(6) Kawase, M.; Kikugawa, Y. J. Chem. Soc., Perkin Trans. 1 1979,
643-645.
(7) Pelter, A.; Rosser, R. M. J. Chem. Soc., Perkin Trans. 1 1984, 717-
720.
(8) Satoh, Y.; Stanton, J. L.; Hutchison, A. J.; Libby, A. H.; Kowalski,
T. J.; Lee, W. H.; White, D. H.; Kimble, E. F. J. Med. Chem. 1993, 36,
3580-3594.
2778
Org. Lett., Vol. 2, No. 18, 2000

excellent results (entry 10), whereas chloroacetic acid (CA)
was an ineffective promoter under the same conditions (entry
12). Smaller excesses of BH3‚pyridine and DCA gave
comparable results in the case of substrate 2a (entry 11),
but larger excesses often proved helpful on some of the more
demanding substrates described below. On the basis of the
results in Table 1, BH3‚pyridine in the presence of DCA was
adopted as the reducing system of choice, as described in
more detail below. The results with BH3‚pyridine and various
carboxylic acids suggest that a minimum acid strength is
necessary to promote oxime reduction by BH3‚pyridine. This
effect is consistent with findings reported by Kikugawa,9
whereby aldehydes were transformed to symmetrical ethers
with BH3‚pyridine in trifluoroacetic acid but not in acetic
acid. Interestingly, dichloroacetic acid also was found to be
a better promoter than acetic acid of sodium cyanoboro-
hydride mediated reduction (Table 1, entry 1 vs entry 14),
although conditions for application of this reducing system
were not optimized.
The scope of the BH3‚pyridine/DCA system with respect
to aldehydes and ketones was examined. First, the conditions
for oxime formation using a variety of ketones and aldehydes
were reexamined, and it was observed that for several
ketones, use of HOAc in TMOF/1,2-dichloroethane (DCE)
gave somewhat better results compared to the conditions
previously used for benzaldehyde (TMOF/THF without
HOAc). Thus, double treatment of 1a with 10 equiv of
aldehyde or ketone (0.5 M) and 3.5 equiv of HOAc (0.2 M)
in 1.3:1 DCE/TMOF for 16-18 h at room temperature was
adopted as a standard protocol for oxime formation. Table
2 summarizes the results from application of this procedure
benzophenones and R-branched acetophenones will likely
require more forcing conditions to induce oxime formation.
The oximes that formed successfully were then subjected
to one or two cycles of reduction with BH3‚pyridine (15
equiv)/DCA (22 equiv) in CH2Cl2 at room temperature for
16-18 h, with the product mixture subjected to benzoylation
followed by cleavage as described above. The results (Table
3) indicate that the majority of cases produce the desired
Table 3. Results for Conversion of 1a to Hydroxamates 5
According to Scheme 1 Using the Standard Protocols (see text)
and Aldehydes or Ketones R1(CdO)R2 a
% unreacted % hydroxamic
aldehyde or ketone
benzaldehyde
p-methoxybenzaldehyde
p-trifluoromethylbenzaldehyde
3-phenylpropionaldehydeb
acetophenone
p-nitroacetophenoneb
N-benzyl-4-piperidinone
benzophenone imine
3-pentanoneb
oxime (2)
acid (5)
<5
<5
21
<5
<5
55
<5
40
ND
>95
>95
79
>95
80
24
90
15
83 (compd 6)
a Data estimated from relative HPLC peak areas monitored at 215 nm.
b Subjected to double reduction (see text).
N-substituted benzohydroxamic acid in good to excellent
purities. However, electron-withdrawing substituents on the
aromatic ring of a starting benzaldehyde or acetophenone
appear to inhibit oxime reduction, and reduction also is quite
sluggish for the benzophenone-derived oxime.
Table 2. Results for Conversion of 1a to Oximes Using the
Standard Protocol (see text) with Aldehydes and Ketones
R1(CdO)R2
To demonstrate the sequence on a preparative scale, 1a
(1.0 g, 1.4 mmol) was reductively alkylated with 3-pentanone
(two cycles of oxime reduction), followed by acylation with
benzoyl chloride and acidolytic cleavage under the conditions
described above. After evaporation of the volatile compo-
nents, the residue (83% pure by HPLC at 215 nm; unacylated
extent of
oxime formationa
aldehyde or ketone (R1/R2)
Ph/H; p-MeO-Ph/H; p-CF3-Ph/H;
Ph-(CH2)2/H; p-NO2-Ph/Me; Et/Et;
ketone ) N-benzyl-4-piperidinone
Ph/Me; Ph/Ph (as imine)
>90%
1
precursor not detected by H NMR) was chromatographed
over silica gel to afford 6 (Scheme 1) in 60% yield and
>95% purity by HPLC monitored at 215 nm. 1H NMR (500
MHz) and high resolution mass spectral data were fully
consistent with the structure.10
70-90%
<20%
Ph/i-Pr; Ph/t-Bu; Ph/c-Pr; Ph/Ph; i-Pr/i-Pr
a Data estimated from HPLC peak areas monitored at 215 nm.
Acknowledgment. We thank Dr. R. M. Scarborough
(COR Therapeutics, S. San Francisco, CA) for valuable input
into this work.
to various aldehydes and ketones, including a number of
sterically or electronically demanding examples. Following
attempted oxime formation, resin samples were washed and
then subjected to benzoylation and cleavage conditions, as
described above, permitting detection of unreacted 1a as
benzohydroxamic acid (in some cases, accompanying hy-
drolysis to benzoic acid, presumably during cleavage, also
was observed). The results show that aliphatic and aromatic
aldehydes, unbranched acetophenones, and unbranched cyclic
and acyclic ketones are good or excellent substrates, whereas
Supporting Information Available: Experimental pro-
cedure for preparation of 6. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL006152G
(10) 1H NMR (500 MHz, CDCl3): δ 0.89 (t, 6H), 1.53 (m, 2H), 1.87
(m, 2H), 3.65 (m, 1H), 7.43-7.51 (m, 5H). High-resolution MS (FAB+):
calcd for C12H18NO2 (M + H) 208.1338; found 208.1337.
(9) Kikugawa, Y. Chem. Lett. 1979, 415-418.
Org. Lett., Vol. 2, No. 18, 2000
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