Reductive cleavage of N-O bonds using samarium(II) iodide in a traceless release strategy for solid-phase synthesis

Article abstract of DOI:10.1021/ol0055162

(Metrix Presented) (i) p-anisoyl chloride, diisopropylethylamine, dichloromethane, 25 °C, 16 h. (ii) DBU, 4-bromobenzyl bromide, toluene, 25 °C, 48 h. (iii) SmI₂/THF, 25 °C, 3 h. A strategy for making amides and ureas using a polymer-supported

Full text of DOI:10.1021/ol0055162

ORGANIC
LETTERS
2000
Vol. 2, No. 10
1349-1352
Reductive Cleavage of N−O Bonds
Using Samarium(II) Iodide in a Traceless
Release Strategy for Solid-Phase
Synthesis
Rebecca M. Myers, Steven P. Langston, Simon P. Conway, and Chris Abell*
UniVersity Chemical Laboratories, Lensfield Road, Cambridge, CB2 1EW, England
ca26@cam.ac.uk
Received January 6, 2000
ABSTRACT
A strategy for making amides and ureas using a polymer-supported hydroxylamine resin as a traceless linker is described. The cleavage of
the linker by samarium(II) iodide is reported for the first time.
New methods in solid-phase synthesis of small organic
molecules continue to develop rapidly and become more
sophisticated.1 The diversity of synthetic targets maintains
the need for new cleavage strategies, with the choice of linker
being an essential part of this synthetic design process. Most
linkers leave behind tell-tale functional groups on cleavage.
Traceless linkers2 are a subgroup of linkers that have been
developed to leave behind, at most, a hydrogen atom at the
attachment point between the molecule and the resin.
The objective of the research described herein was to
develop a simple traceless linker that could be used for
bidirectional elaboration from a central nitrogen atom. To
this end we have extended the usefulness of polymer-
supported hydroxylamine. This linker has previously been
described by others and has been used in the synthesis of
tripeptide and sulfonamido hydroxamic acid derivatives,3 and
in the synthesis of a range of carbonyl-containing com-
pounds.4 An N-Fmoc-aminooxy-2-chlorotrityl-polystyrene
resin has also been reported. On deprotection it reveals a
chlorotrityl hydroxylamine linker and it has been used in
the synthesis of peptidyl hydroxamic acids.5 In these
examples, the release strategy either involved C-O bond
cleavage with trifluoroacetic acid or C-N bond cleavage
with lithium aluminum hydride to give hydroxamic acids
and aldehydes,4b respectively. To cleave in a traceless
(1) (a) Baldwin, J. J.; Burbaum, J. J.; Sigal, N. Current Trends in Organic
Synthesis; Scholastico, C., Nicotra, F., Eds.; Academic/Plenum Press: New
York, 1999; pp 71-75. For comprehensive reviews on combinatorial library
synthesis, see the following. (b) Dolle, R. E.; Nelson, K. H. J. Comb. Chem.
1999, 1, 235-282. (c) Balkenhohl, F.; Bussche-Hu¨nnefeld, C.; Lansky A.;
Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-2337. (d) Ellman,
J. A.; Gallop, A. Curr. Opin. Chem. Biol. 1998, 2, 317-319.
(2) (a) Reitz, A. B. Curr. Opin. Drug Discuss. DeV. 1999, 2, 358-364.
(b) Paio, A.; Zaramella, A.; Feritto, R.; Conti, N.; Marchioro, C.; Seneci,
P. J. Comb. Chem. 1999, 1, 317-325. (c) Schiemann K.; Showalter, H. D.
H. J. Org. Chem. 1999, 64, 4972-4975. (d) Wilson, L. J.; Klopfenstein S.
R.; Li, M. Tetrahedron Lett. 1999, 40, 3999-3402. (e) Steiber, F.; Grether,
U.; Waldman, H. Angew. Chem., Int. Ed. Engl. 38, 1073-1077. (f) Craig,
D.; Robson, M. J.; Shaw, S. J. Synlett 1998, 12, 1381-1383. (g) Bra¨se, S.;
Enders, D.; Ko¨bberling J.; Avemaria, F. Angew. Chem., Int. Ed. 1998, 37,
3413-3415.
(3) Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M. Tetrahedron
Lett. 1996, 37, 8045-8048.
(4) (a) Salvino, J. M.; Morton, G. C.; Mason, H. J. U.S. Pat. WO 98/
29376. (b) Salvino, J. M.; Mervic, M.; Mason, H. J.; Kiesow, T.; Teager,
D.; Airey, J.; Labaudiniere, R. J. Org. Chem. 1999, 64, 1823-1830.
(5) Mellor, S. L.; McGuire, C.; Chan, W. C. Tetrahedron Lett. 1997,
38, 3311-3314.
10.1021/ol0055162 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/28/2000

manner, it is necessary to cleave the N-O bond6 of the
hydroxylamine instead (Figure 1).
reductive cleavage of the N-O bond of 3 was achieved using
0.1 M samarium(II) iodide in THF. The cleavage went to
completion at room temperature within 5 min, giving N-(4-
bromo-benzyl)-4-methoxybenzamide 4 in high yield (92%).
For the solid-phase chemistry the hydroxylamine linker
was prepared from Wang resin 5 using an established
literature procedure.4b This involved coupling N-hydroxy-
phthalimide to the hydroxymethyl group on the resin under
Mitsunobu conditions to give 6. The phthalimido group was
removed with a 40% aqueous solution of methylamine and
THF (Scheme 2). The loading of 7 was 1.18 mmol g-1, based
Scheme 2. Hydroxylamine Resin Prepared from Wang
Resin.13 a
Figure 1. Cleavage options for functionalized hydroxylamine resin.
Samarium(II) iodide7 has been used for reductive cleavage
of NsO bonds in solution,8 including those in hydroxyl-
amines and hydroxamic acids.9 This reagent is increasingly
being used in a variety of synthetic transformations10 and
can be purchased commercially as a 0.1 M solution in THF
(a suitable solvent in terms of resin swelling properties). It
can also be prepared in similar concentrations.11 The use of
samarium(II) iodide has the additional benefit that the
cleavage reaction does not require acidic conditions. This
paper describes our development of a samarium(II) iodide
induced reductive cleavage of a hydroxylamine linker for
the solid-phase synthesis of amides and ureas.
a (i) N-Hydroxyphthalimide, PPh3, DIAD, THF, 0 °C - 25 °C,
16 h; (ii) 40% aqueous methylamine, THF, 25 °C, 16 h.
on nitrogen analysis, and corresponded to a yield in excess
of 90%. The hydroxylamine linker was also prepared from
Merrifield resin (1 mmol g-1) with less success. The
N-hydroxyphthalimide was loaded onto the resin using
sodium hydride and catalytic tetrabutylammonium iodide.
Removal of the phthalimido group with hydrazine hydrate
gave the hydroxylamine linker with a substantially lower
loading of 0.22 mmol/g (by Fmoc analysis12 at 290 nm).
The utility of this traceless cleavage strategy was dem-
onstrated by the synthesis of a range of amides and ureas,
8-15 (Scheme 3).
An initial study was carried out in the solution phase
(Scheme 1). Benzylhydroxylamine 1 was used as a model
Scheme 1. Solution-Phase Studya
The procedure involved initial acylation of the Wang-based
hydroxylamine resin, which introduced the first level of
diversity (step i, Scheme 3). The acylations were carried out
using acid chlorides, a benzoic acid derivative, or a carbamyl
chloride.
Scheme 3. Solid-Phase Synthesis of Compounds 8-1513 a
a (i) p-Anisoyl chloride, DIPEA, DCM, 25 °C, 45 min (72%);
(ii) 4-bromobenzyl bromide, DBU, toluene, 0-25 °C, 45 min
(40%); (iii) SmI2 (0.1 M), THF, 25 °C, 5 min (92%).
for the polymer-supported hydroxylamine linker 7. Rapid
acylation of benzylhydroxylamine 1 with p-anisoyl chloride
gave 2 (72%). Alkylation with 4-bromobenzyl bromide using
DBU as the base gave 3 in modest yield (40%). Subsequent
(6) For a discussion of the reduction of N-O bonded groups, see:
Gilchrist, T. L. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Vol 8, pp 390-395.
(7) Girard, P.; Namy, J. L.; Kagan, H. B. J Am. Chem. Soc. 1980, 102,
2693-2698.
a (a) Acid chloride, DIPEA, DCM or (b) carboxylic acid, DIC,
HOBt, DMF, at 25 °C, 16 h; (ii) DBU, alkyl bromide, toluene, 25
°C, 48 h; (iii) 0.1 M SmI2 in THF, 25 °C, 3 h.
1350
Org. Lett., Vol. 2, No. 10, 2000

disappeared. The products were obtained in modest yields
and in good to excellent purity (Table 2).
Table 1. Definitions of R1 and R2 in Products 8-15
R1
R2
product
The procedure for the preparation of hydroxylamine resin
7,17 amide 11,18 and urea 1519 are given in the references
cited.
4-methoxyphenyl
n-hexane
4-bromobenzyl
4-bromobenzyl
4-bromobenzyl
isobutyl
8
9
4-iodophenyl
4-iodophenyl
4-iodophenyl
4-iodophenyl
diphenylurea
diphenylurea
10
11
12
13
14
15
(8) (a) Natale, N. L. Tetrahedron Lett. 1982, 23, 5009-5012. (b)
Mukaiyama, T.; Yorozu, K.; Kato, K.; Yamada, T. Chem. Lett. 1992, 181-
184. (c) Zhang, Y.; Lin, R. Synth. Commun. 1987, 17, 329-332.
(9) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995,
36, 7419-7422.
(10) For an early review, see: Soderquist, J. A. Aldrichimica Acta 1991,
24, 15-23.
allyl
propargyl
allyl
isobutyl
(11) Imamoto, T.; Ono, M. Chem. Lett. 1987, 501-502.
(12) A procedure for substitution measurement of Fmoc resins is given
in the following: Bennett, W. D.; Christenden, J. W. AdVanced Chemtech
Handbook of Combinatorial and Solid-Phase Organic Chemistry; 1998; p
330.
(13) Abbreviations: dichloromethane (DCM), N,N-diisopropylethylamine
(DIPEA), N-hydroxybenzotriazole hydrate (HOBt), diisopropylcarbodiimide
(DIC), diisopropyl azodicarboxylate (DIAD), 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU).
(14) HPLC purity at 254 nm unless noted otherwise.
(15) HPLC purity at 220 nm.
(16) Purity determined from the peak area in the LC trace over UV range
215-330 nm.
Alkylation of the hydroxamic nitrogen in the second step
was achieved using the base DBU and the isobutyl, prop-
argyl, allyl, or 4-bromobenzyl bromides in toluene. Reductive
cleavages were performed on the resulting dried resins under
anhydrous conditions. Products 8-15 (Table 1) were ob-
tained by cleavage with samarium(II) iodide over 3 h,
although product release could be detected by TLC and
HPLC after only a few minutes in most cases. The carbonyl
stretches in the FTIR spectra of the cleaved resins had
(17) Procedure for the preparation of the hydroxylamine linker from
Wang resin.4b Wang resin (100-200 mesh, 1.29 mmol/g, 25 g, 32.25 mmol)
was suspended in THF (250 mL). The suspension was chilled to 0 °C.
Triphenylphosphine (16.92 g, 64.50 mmol, 2 equiv) was added followed
by N-hydroxyphthalimide (26.13 g, 161.25 mmol, 5 equiv). After stirring
at 0 °C for 15 min, diisopropyl azodicarboxylate (12.70 mL, 64.50 mmol,
2 equiv) was added slowly. The suspension was warmed to rt, and stirring
was continued for a total of 12 h. The suspension was filtered, and the
resin collected in a sintered funnel. The resin was washed with methanol,
water, ethyl acetate, and dichloromethane (minimum of 2 × 100 mL of
each) until the resin was free from discoloration and was cream in color.
Table 2. Products 8-15 Obtained Using SmI2-Induced
Reductive Cleavage
ν
max/cm-1 (gel) 1789 (CdO), 1727 (CdO). The moist resin was transferred
to a 1 L conical flask and stirred in a solution of THF (500 mL) and a 40%
aqueous methylamine solution (250 mL) for 16 h. The resin was washed
as previously described and dried under high vacuum for 4 h (24.9 g). νmax
/
cm-1 (gel) 3323 (ONH2). Anal. Calcd: N, 1.74. Found: N, 1.95. Loading
1.18 mmol/g (based on N anal.). Yield 91% (based on N analysis).
(18) 4-Iodo-N-isobutylbenzamide (11). Hydroxylamine resin (1.00 g,
1.18 mmol) was suspended in a solution of 4-iodobenzoic acid (0.94 g,
3.78 mmol), diisopropylcarbodiimide (0.58 mL, 3.78 mmol), and N-
hydroxybenzotriazole hydrate (0.59 g, 3.78 mmol) in DMF (10 mL). The
suspension was shaken at 25 °C for 16 h. νmax/cm-1 1668 (CdO). The
resin was washed with methanol, ethyl acetate, and dichloromethane (5 ×
25 mL of each) and then dried under high vacuum for 16 h. The resin was
then suspended in a solution of DBU (0.94 mL, 6.3 mmol) in toluene (15
mL), and isobutyl bromide (1.33 g, 12.2 mmol) was added. The suspension
was shaken at 25 °C for 48 h. The resin was washed and dried as described
above. The resin (1.21 g, 1.05 mmol) was preswollen with THF (2.1 mL),
and samarium(II) iodide (0.1 M in THF, 20.99 mL, 2.10 mmol) was added.
The reaction suspension was shaken at 25 °C for 3 h. The resin was filtered
off and rinsed with dichloromethane (5 × 10 mL), and the cleavage solution
and washings were collected. The filtrate was evaporated to give a dark
yellow residue which was redissolved in a solution of diethyl ether (25
mL), 1 M HCl (20 mL), and 10% aqueous sodium thiosulfate (5 mL). The
mixture was transferred to a separating funnel and shaken until it became
colorless. The organic layer was collected, and the aqueous layer was
extracted with diethyl ether (2 × 10 mL). The combined organic layers
were washed with brine (2 × 10 mL) and dried over magnesium sulfate.
The solid obtained after evaporation was redissolved in the minimum amount
of dichloromethane (ca. 0.3-0.5 mL) and filtered through a short pad of
silica (ca. 3 cm in a 1.5 cm diameter column, eluting with 20% ethyl acetate
in hexanes). The filtrate was collected and evaporated to afford 4-iodo-N-
isobutylbenzamide 11 (49 mg, 33%): Rf 0.63 [vis UV, ethyl acetate/hexanes
(1:1)]; νmax/cm-1 3305 (NH), 1633 (CdO); 1H NMR (500 MHz, CDCl3) δ
0.96 (6 H, d, J ) 6.5, (CH3)2C), 1.86-1.91 (1 H, m, (CH3)2CH), 3.27 (2
H, dd, J ) 6.5, 6.5, CH2), 6.06 (1 H, s, br, NH), 7.74 (2 H, d, J ) 8.5,
Ar-H), 7.77 (2 H, d, J ) 8.5, Ar-H); 13C NMR (500 MHz, CDCl3) δ
19.89 (CH3), 28.34 (CH), 47.15 (CH2), 128.17 (CH), 137.52 (CH), 163.4
(CdO); MS (ES) m/z ) 304.0 (M + H+, 100%), 326.0 (M + Na+, 12%);
LCMS tR 5.0 min; HPLC tR 14.4 min, 99.2% (254 nm, TSK gel Oligio
DNA RP; solvent A acetonitrile + 0.1% TFA, solvent B milliQ water +
0.1% TFA, gradient 5-95% solvent A over 15 min).
Org. Lett., Vol. 2, No. 10, 2000
1351

Acknowledgment. We thank Peptide Therapeutics for
CASE Award funding to R.M.M.
Supporting Information Available: Full experimental
details and characterization for compounds 2, 3, 4, and 7-15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) 3-Isobutyl-1,1-diphenylurea (15). Hydroxylamine resin (1.00 g,
1.18 mmol) was suspended in a solution of diphenylcarbamyl chloride (0.84
g, 3.78 mmol) and N,N-diisopropylethylamine (0.67 mL, 3.78 mmol) in
dichloromethane (10 mL). The suspension was shaken at 25 °C for 16 h.
The resin was washed with methanol, ethyl acetate, and dichloromethane
OL0055162
(5 × 25 mL of each) and then dried under high vacuum for 16 h. νmax
/
cm-1 (gel) 3372 (NH), 1697 (CdO). The resin was suspended in a solution
of DBU (0.94 mL, 6.3 mmol) and toluene (15 mL), isobutyl bromide (1.33
mL, 12.2 mmol) was added, and the suspension was shaken at 25 °C for
48 h. The resin was washed and dried as described above. νmax/cm-1 (gel)
1690 (CdO). The resin (0.78 g, 0.97 mmol) was preswollen with THF
(1.9 mL), and samarium(II) iodide (0.1 M in THF, 19.34 mL, 1.93 mmol)
was added. The reaction suspension was shaken at 25 °C for 3 h. The resin
was filtered off and rinsed with dichloromethane (5 × 10 mL), and the
cleavage solution and washings were collected. The solution was evaporated
to give a dark yellow residue which was redissolved in a solution of diethyl
ether (25 mL), 1 M HCl (20 mL), and 10% aqueous sodium thiosulfate (5
mL). The mixture was transferred to a separating funnel and shaken until
it became colorless. The organic layer was collected and the aqueous layer
extracted with diethyl ether (2 × 10 mL). The combined ethereal layers
were washed with brine (2 × 10 mL) and then dried over magnesium sulfate.
The solid obtained after evaporation was dissolved in the minimum amount
of dichloromethane (ca. 0.3-0.5 mL) and then filtered through a short pad
of silica (ca. 3 cm in a 1.5 cm diameter column, eluting with 50% ethyl
acetate/hexanes). The filtrate was collected and evaporated to afford
3-isobutyl-1,1-diphenylurea 15 (58 mg, 31%): Rf 0.55 [vis UV, ethyl acetate/
1
hexanes (1:1)]; νmax/cm-1 3288 (NH), 1643 (CdO); H NMR (500 MHz,
CDCl3) (two rotamers in a ratio of 0.2:0.3 assigned using HMQC as A and
B where possible) δ 0.78 (3 H, d, J 7, CH3), 0.86 (3 H, d, J 7, CH3), 1.70-
1.77 (0.4 H, m, CH3-CH, A), 1.90-1.98 (0.6 H, m, CH3-CH, B), 3.05
(0.4 H, m, CH2-N, A), 3.11 (0.6 H, d, J ) 7, CH2-N, B), 4.56 (0.6 H, s,
NH, A), 6.52 (0.4 H, s, NH, B), 7.10-7.38 (10 H, m, Ar-H); 13C NMR
(500 MHz, CDCl3) (according to the HMQC and APT spectra, all carbon
atoms except the aromatic carbons are seen as two rotamers forms and
have been assigned as A and B where possible in relation to A and B in
the proton spectrum) δ 19.7 (CH3, A), 19.8 (CH3, B), 25.9 (CH, B), 28.5
(CH, A), 47.9 (CH2, A), 58.8 (CH2, B), 125.4 (Ar), 125.6 (Ar), 125.8 (Ar),
127.1 (Ar), 129.0 (Ar), 142.6 (Ar), 143.7 (Ar), 156.0 (CdO), 161.7 (Cd
O); MS (ES) m/z ) 269.2 (M + H+, 100%); LCMS tR 5.0 min, purity 99%
estimated by LC area (UV 215-330 nm).
1352
Org. Lett., Vol. 2, No. 10, 2000