Parallel synthesis of aldehydes and ketone facilitated by a new solid- phase Weinreb amide

Article abstract of DOI:10.1021/jo981431r

This paper describes a novel supported Weinreb amide resin that facilitates parallel synthesis of aldehydes and ketones on a scale useful for chemical library synthesis. This new resin makes it possible to produce custom aldehydes and ketones from a wide range of carboxylic acids, including N-BOC-amino acids. A variety of commercially unavailable aldehydes are easily synthesized in parallel and obtained in high purity via a simple filtration workup, thus facilitating parallel synthesis of lead optimization libraries that typically require custom synthesis of aldehyde intermediates for development of structure-activity relationships. To demonstrate the utility of this method, we synthesized a small library based on a supported Horner- Emmons reagent. This is the first time it has been shown that aldehydes generated via a supported Weinreb amide could be used directly as reagents in chemical library synthesis employing moisture-sensitive reactions. The analogous solution reaction is not suited for parallel synthesis because of the laborious extractive workup procedure necessary and, at times, the instability of these reactive intermediates.

Full text of DOI:10.1021/jo981431r

J . Org. Chem. 1999, 64, 1823-1830
1823
P a r a llel Syn th esis of Ald eh yd es a n d Keton e F a cilita ted by a New
Solid -P h a se Wein r eb Am id e†
J oseph M. Salvino,* Miljenko Mervic, Helen J . Mason, Terence Kiesow, David Teager,
J ohn Airey, and Richard Labaudiniere
Lead Discovery Department, Rhone-Poulenc Rorer, 500 Arcola Road, Collegeville, Pennsylvania 19426
Received J uly 22, 1998
This paper describes a novel supported Weinreb amide resin that facilitates parallel synthesis of
aldehydes and ketones on a scale useful for chemical library synthesis. This new resin makes it
possible to produce custom aldehydes and ketones from a wide range of carboxylic acids, including
N-BOC-amino acids. A variety of commercially unavailable aldehydes are easily synthesized in
parallel and obtained in high purity via a simple filtration workup, thus facilitating parallel
synthesis of lead optimization libraries that typically require custom synthesis of aldehyde
intermediates for development of structure-activity relationships. To demonstrate the utility of
this method, we synthesized a small library based on a supported Horner-Emmons reagent. This
is the first time it has been shown that aldehydes generated via a supported Weinreb amide could
be used directly as reagents in chemical library synthesis employing moisture-sensitive reactions.
The analogous solution reaction is not suited for parallel synthesis because of the laborious extractive
workup procedure necessary and, at times, the instability of these reactive intermediates.
4
In tr od u ction
Horner-Emmons reaction and in the Ugi four-compo-
5
nent condensation. The purpose and focus of this work
The recent development of parallel and combinatorial
chemical library synthesis has created a renewed interest
in polymeric solid-phase reagents. They offer the ad-
vantage of easy separation from low molecular weight
reactants or products by filtration or selective precipita-
tion and are very suitable for automation of chemical
library synthesis.
Reduction of Weinreb amides is a classical method for
converting carboxylic acids into aldehydes and ketones.2
This paper describes a novel supported Weinreb amide3
that greatly facilitates parallel synthesis of aldehydes
compared to classical solution methods. The advantage
of using the supported reagent as opposed to the solution
method becomes apparent during the workup of the
reaction. The solid-phase method offers an extremely
simple filtration workup in contrast to the aqueous
extractive workup necessary for the solution method. The
solid-phase method, although not suited for multigram
quantities of a few select aldehydes, becomes the method
of choice when greater than 20 aldehydes are needed on
a multi-milligram scale.
was not development of a method for the preparation of
individual aldehydes that would be superior to the
existing solution method. The purpose was to develop a
method that would allow a simple parallel synthesis of
greater than 20 aldehydes in multimilligram quantities
of high enough purity to be used directly as intermediates
in chemical library synthesis. The emphasis on purity of
the produced aldehydes is based on the following con-
siderations. First, it was quickly revealed that one person
could not rapidly generate the required number of
aldehydes by the solution method as it was classically
practiced, due to the nature of the aqueous extractive
workup procedure. The second consideration was that
many of the desired aldehydes were unstable, and
especially for this class of aldehydes it was necessary to
use a method that facilitated the workup and handling
of these unstable reagents.
Since the goal of this work was to develop a facile
method to produce aldehydes as reagents in chemical
library synthesis, it was quite important that the utility
of the method be demonstrated. Therefore, a small library
was executed using a supported Horner-Emmons reac-
tion. The supported Horner-Emmons reaction is sensi-
tive to moisture and purity of the aldehyde; thus, it was
felt this reaction would be a good validation of the
aldehyde synthesis.
1
Custom, commercially unavailable aldehydes and ke-
tones were sought as building blocks for use in chemical
library synthesis of acrylic acids based on a solid-phase
†
Dedicated to the memory of George N. Salvino (6/24/29-10/27/
9
8).
(
1) (a) Parlow, J . J . Tetrahedron Lett. 1995, 36, 1395-1396. (b)
Because this new supported version of Weinreb amides
facilitates the parallel conversion of carboxylic acids to
aldehydes or ketones of high enough purity to be used
directly in library synthesis, this method provides a fast
Akelah, A.; Sherrington, D. C. Chem Rev. 1981, 81, 557. (c) Ford, W.
T.; Blossey, E. C. In Preparative Chemistry using Supported Reagents;
Laszlo, P., Ed.; Academic Press: California, 1987; pp 193-212. (d)
Frechet, J . M. J .; Warnock, J .; Farrall, M. J . J . Org. Chem. 1978, 43,
618-2621. (e) Cainelli, G.; Cardillo, G.; Orena, M.; Sanhi, S. J . Am.
Chem. Soc. 1976, 98, 6737.
2
(
2) Nahm S.; Weinreb, S.Tetrahedron Lett. 1981, 22, 3815-3818.
(4) Salvino, J . M.; Kiesow, T. J . Automated Parallel Synthesis of
Olefins. In Proceedings of the International Symposium on Laboratory
Automation and Robotics, Zymark Corp.: Hopkinton, MA, 1997; pp
99-106.
(5) (a) Gokel, G.; Ludke, G.; Ugi, I. In Isonitrile Chemistry; Ugi, I.,
Ed.; Academic Press: New York, 1971; pp 145-199. (b) Ugi, I. Angew
Chem., Int. Ed. Engl. 1962, 1, 8-28. (c) Ugi, I.; Domling, A.; Horl, W.
Endeavor 1994, 18, 115.
3
a,b
3c
(3) In the course of this work, Martinez
and Armstrong reported
supported Weinreb amides linked to the resin via a C-N bond. (a)
Fehrentz, J .-A.; Paris, M.; Heitz, A.; Velek, J .; Liu, C.-F.; Winternitz,
F.; Martinez, J . Tetrahedron Lett. 1995, 36, 7871-7874. (b) Fehrentz,
J .-A.; Paris, M.; Heitz, A.; Velek, J .; Winternitz, F.; Martinez. J . J .
Org. Chem. 1997, 62, 6792-6796. (c) Dinh, T. Q.; Armstrong, R. W.
Tetrahedron Lett. 1996, 37, 1161-1164.
1
0.1021/jo981431r CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/19/1999

1
824 J . Org. Chem., Vol. 64, No. 6, 1999
Salvino et al.
Sch em e 1a
a
Key: (i) Wang resin, 1 (18.35 g; 20 mmequiv), THF (450 mL), triphenylphosphine (17.74 g; 60 mmol), N-hydroxyphthalimide (16.31
g; 100 mmol), diisopropyl azodicarboxylate (11.8 mL; 60 mmol), 0-25 °C, 12 h; (ii) THF (400 mL), 40% aqueous methylamine solution
(200 mL; 2.31 mol), 40 °C for 2 h, then 25 °C for 12 h; (iii) resin 3 (200 mg; ca. 0.2 mmol), DMF (3 mL), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI, 115 mg; 0.6 mmol), 4-nitrophenylacetic acid (115 mg; 0.6 mmol), 25 °C, 6 h; (iv) resin 4 (220 mg;
ca. 0.2 mmol), DCM (2 mL), H2O (0.02 mL), TFA (2 mL), 25 °C, 1 h.
Sch em e 2
of the alkylation using elemental analysis. Thus, 4-bro-
mo- and 4-chlorobenzyl bromides were used to aid in
monitoring the progress of the solid-phase N-alkylation
reaction by elemental analysis of the resin. In addition,
acid cleavage of the N-benzylhydroxamic acid from the
solid support followed by classical solution analytical
1
methods ( H NMR, LC/MS) was also used to optimize the
N-alkylation reaction. It was found that the N-alkylation
reaction worked well using a slight excess of DBU in
anhydrous toluene followed by the alkylating reagent.
3
Other conditions such as CsCO /DMF or DIEA/THF did
and easy access to a large number of currently unavail-
able compounds of interest in medicinal chemistry.
not give complete alkylation or were not as clean. Several
reducing agents, organometallic reagents, and workup
procedures as well as a wide variety of carboxylic acids
were studied to explore the scope of this solid-phase
reagent.
Resu lts a n d Discu ssion
This supported Weinreb amide synthesis was initially
envisioned on the basis of a simple modification of a
polymeric hydroxylamine resin that was developed in our
The focus of this method was the facile preparation of
aldehydes and ketones with an emphasis on the purity
of the crude products released from the resin. Clearly,
for this method to have utility a structurally diverse set
of carboxylic acids must be converted to aldehydes with
a purity enabling them to work well in further chemical
reactions without the need for purification.11 The most
important optimization criterion was the purity of alde-
hydes and ketones released from the resin. It was deemed
of great importance to validate any method that was
developed by subjecting the crude aldehydes produced
laboratory for the conversion of carboxylic acids to
hydroxamic acids,6,7 exemplified in Scheme 1.
The polymeric Wang-O-hydroxylamine resin (3) has
been synthesized by a straightforward procedure provid-
ing kilogram quantities of resin. N-Hydroxyphthalimide
8
was coupled to Wang resin (1) using Mitsunobu condi-
9
tions. The phthalimido protecting group was removed
by methylaminolysis in THF instead of the commonly
used hydrazinolysis procedure, offering significant safety
4
advantages on the kilogram scale.10 The Wang-O-hy-
to the supported Horner-Emmons synthesis protocol.
The reduction conditions employed were to suspend the
N-alkylated, N-acylated resin in THF at 0 °C and treat
it with LAH for 30 min to generate the chelated complex.
Workup and product release was accomplished by treat-
ment with aqueous potassium hydrogensulfate followed
by saturated Rochelle salt. The reaction mixture was
filtered through a short plug of silica gel with a bed of
anhydrous sodium sulfate on the top to dry the reaction
mixture. The resulting aldehydes were thus generated
in acceptable yields of 30-50% and in excellent purity.
Typically, 3-4 g of resin would generate 250-300 mg of
aldehyde. Using simple glass-jacketed reaction vessels
fitted with glass frits for filtration, one chemist could
easily generate 20 aldehydes in a morning and use them
immediately in a chemical reaction that afternoon.
The use of the N-benzylated-N-acylated resin produced
the purest aldehydes or ketones. This may be due to
increased stability of the resulting aluminum complex
droxylamine resin (3) may be directly acylated with a
carboxylic acid and then cleaved using 50% TFA in DCM
6
as a general means to generate hydroxamic acids (5).
Acylation of the Wang-O-hydroxylamine resin (3) fol-
lowed by N-alkylation was explored as a general route
to supported Weinreb amides (Scheme 2).
An analytical method was needed to monitor the
N-alkylation reaction on the solid phase. It was desired
to use a method that monitored the N-alkylation directly.
A convenient method is to incorporate a bromine or
chlorine atom in the molecule used as the electrophile
in the alkylation reaction and then monitor the progress
(
6) (a) Groneberg, R. et al. (Rhone Poulenc Rorer) US Patent Appl.
0/009,484. (b) International Patent Appl. PCT/US97/00264. (c) See
also: Prasad, V. V. K.; Warne, P. A.; Lieberman, S. J . Steriod Biochem.
983, 18, 257.
7) During the course of this work the following appeared in the
6
1
(
literature: (a) PCT Appl. WO96/26223. (b) Floyd, C. D.; Lewis, C. N.;
Patel, S. R.; Whittaker, M. Tetrahedron Lett. 1996, 37, 8045-8048.
(
c) Richter, L. S.; Desai, M. C. Tetrahedron Lett. 1997, 38, 321-322.
(
(
(
8) Wang, S. S. J . Am. Chem. Soc. 1973, 95, 1328-1333.
(11) Previously reported versions of supported Weinreb amides3c
were shown to produce a significant amount of the undesired alcohol
as a side product.
9) Mitsunobu, O. Synthesis 1981, 1-28.
10) Wolf, S.; Hasan, S. K. Can. J . Chem. 1970, 48, 3572-3579.

Synthesis of Aldehydes, Ketones, and Hydroxamic Acids
J . Org. Chem., Vol. 64, No. 6, 1999 1825
Ta ble 1. Ald eh yd es Obta in ed by Red u ctive Clea va ge
a
Purity estimated by HPLC (A% at UV220). b Purity estimated by 1H NMR.
Sch em e 3
surrounded by the large lipophilic aromatic group. 4-Bro-
mobenzyl or 4-chlorobenzyl was used only as an analyti-
cal handle to aid in monitoring the progress of the
N-alkylation reaction of 4 by elemental analysis (the
bromobenzyl, chlorobenzyl and benzyl moieties were
essentially equivalent for aldehyde processing). The
structure and isolated yields of a diverse set of aldehydes
obtained by reductive cleavage are listed in Table 1.
Analysis of Table 1 reveals an interesting observation.
Carboxylic acids containing secondary or tertiary nucleo-
philic nitrogen atoms tended to give lower yields or no
desired aldehyde product (% yield lower than 30%; i.e.,
see 7a ,d ,e,l,m ). These trends, although not outstandingly
obvious, raised a concern about the method for the
potential to alkylate the carboxylic acid substrate if it
contained a nucleophilic amine. Furthermore, during the
optimization of the aldehydes derived from HN-BOC
amino acids this method failed. The failure was at-
tributed to competing N-alkylation of the NH-BOC
moiety suggested by examination of the MS and the H
NMR spectrum of the aldehydes attempted using this
general reaction sequence in Scheme 3.
The synthesis of aldehydes derived from N-BOC amino
acids was highly desired. Therefore, to avoid the problem
of undesired N-alkylation and to broaden the scope of the
reaction a second route (Scheme 4) was developed in
which the alkylation of the Wang-O-hydroxylamine resin
to accomplish this goal such as direct alkylation, reduc-
tive alkylation of the oxime, or N-alkylation of a carbam-
ate derivative. Direct alkylation of the resin resulted in
either poor conversion to monoalkylated resin or in
dialkylation. Reductive alkylation of the oxime was
problematic. Different reducing agents (such as NaBH-
(OAc) , NaCNBH , NaBH , or LiBHEt ) produce varying
3
3
4
3
ratios of no reduction, partial reduction to the desired
hydroxylamine, and over-reduction to the amine resulting
in cleavage from the resin. Fortunately N-alkylation of
the Alloc derivative of the hydroxylamine resin (11)
successfully generated the desired monoalkylated resin
(13) after Alloc removal (Scheme 4). Note that the
4-bromobenzyl moiety could no longer be used as an
analytical handle because the bromine interfered in the
Pd-catalyzed Alloc deprotection step.
1
The N-benzylhydroxylamine resin (13) was acylated
with N-BOC phenylalanine, treated with LAH, and then
worked up as previously described. The C-terminal
(3) precedes acylation. Several methods were envisioned

1
826 J . Org. Chem., Vol. 64, No. 6, 1999
Salvino et al.
Sch em e 4a
Ta ble 2. Red u ctive Clea va ge to Ald eh yd es Con ta in in g a
Secon d a r y Nitr ogen
a
Key: (i) hydroxylamine resin (3) (2 g; 2.0 mmol), allylchloro-
formate (265 mg; 2.2 mmol), DCM (15 L), diisopropylethylamine
284 mg, 2.2 mmol), rt, 12 h; (ii) resin 11 (2.0 mmol), toluene (15
(
mL), DBU (1.5 g; 1.5 mL; 10 mmol), benzyl bromide (1.7 g; 10
mmol), rt, 70 h; (iii) resin 12 (ca 2.0 mmol), THF (6 mL), DMSO
(6 mL), 0.5 N HCl (3 mL), Pd (Ph3P)4 (347 mg; 15 wt %),
morpholine (4.3 mL), rt, 12 h; (iv) resin 13 (1 mmol), N-BOC
phenylalanine (3 mmol), EDCI (3 mmol), DMF, rt, 12 h; (v) resin
1
4 (1 mmol), anhydrous THF, LAH (1M in THF; 2 mmol), 0 °C,
3
0 min then acidic workup.
aldehyde was generated in excellent purity in yields
3
comparable to those obtained by Martinez. Table 2 lists
a set of aldehydes obtained via reductive cleavage utiliz-
ing this method.
To validate the utility of this method as a means to
synthesize aldehydes in parallel for use as reagents in
library production, crude aldehydes were used directly
in a supported Horner-Emmons reaction. The supported
Horner-Emmons reaction was a good test reaction to
determine the quality of these aldehydes due to the
nature of the reaction. Thus, 4-bromo-3-methyl benzal-
dehyde, 3,4-dimethyl cinnamaldehyde, and N-phenylan-
thranilic aldehyde were generated (Scheme 2) and were
used crude in the supported Horner-Emmons reaction
(Table 3).
The aldehydes reacted well in the supported Horner-
Emmons synthesis and after TFA cleavage from the resin
produced substituted acrylic acids in excellent purity.
This confirmed the high degree of purity of these alde-
hydes and served to validate our process, demonstrating
its usefulness for library production. These aldehydes
were also successfully used in combinatorial libraries
based on the Ugi 4-component condensation (data not
shown). On the basis of these results, resin 13 has been
shown to be a useful and general means to produce
aldehydes in a parallel fashion for use in a variety of
chemical libraries (Scheme 5).
a
Purity estimated by HPLC (A% at UV220 or UV254). b Purity
estimated by 1H NMR.
Ketones may also be formed by reaction of the sup-
ported Weinreb amides with Grignard reagents. A cur-
sory examination using ethyl Grignard suggested the
potential of this conversion (Table 4). Future work in our
laboratory will concentrate on broadening the scope of
this process with a focus on library production.
Exp er im en ta l Section
Gen er a l Meth od s. The reactions were carried out on a
Burrell wrist action shaker Model 75. Solvents used were EM
Science of OmniSolv distilled grade unless specified otherwise.
The following abbreviations were used: DCM ) dichlo-
romethane, DMF ) dimethylformamide, THF ) tetrahydro-
furan, Et
DIEA ) N,N-diisopropylethylamine, DBU ) 1,8-diazabicyclo-
5.4.0]undec-7-ene, TFA ) trifluoroacetic acid, EDCI ) 1-(3-
2
O ) diethyl ether, DMSO ) dimethyl sulfoxide,
Con clu sion
[
The N-benzyl derivative of resin 3, resin 13 is a new
tool useful in the synthesis of aldehydes or ketones for
use in chemical libraries. The supported Weinreb amide
facilitates parallel synthesis of aldehydes for multimil-
ligram scale production. The scope of the reaction has
been demonstrated to be quite wide, no alcohol side
product is observed,11 and the purity of the resulting
aldehyde or ketone is such that it may be used directly
as a building block in combinatorial or parallel synthesis
of chemical libraries.
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, LAH
) lithium aluminum hydride, LiHMDS ) lithium hexameth-
yldisilizane. 1H NMR spectra were recorded on a 300 MHz
ARX Bruker spectrometer in CDCl unless otherwise stated.
3
Mass spectra were recorded on Finnigan 4500 EI and Sciex
API 3 IS spectrometers.
4
-O-(Me t h ylh yd r oxyla m in e )p h e n oxym e t h ylcop oly-
styr en e-1%-d ivin ylben zen e)r esin (100-200 Mesh ) (3). A
-L jacketed reactor with a bottom valve and overhead stirrer
(
1
(Ace catalog no. 8090) was charged with Wang resin (18.35 g;
20 mmol) and anhydrous THF (450 mL). This mixture was

Synthesis of Aldehydes, Ketones, and Hydroxamic Acids
J . Org. Chem., Vol. 64, No. 6, 1999 1827
Ta ble 3. Solid -P h a se Hor n er -Em m on s Rea ction s w ith
the temperature at <5 °C. When the addition was complete,
the stirred mixture was allowed to warm slowly to room
temperature and stirred overnight. As much of the reaction
liquors as possible was removed by aspiration through the dip
tube as above. The resin was washed by charging DMF (200
mL), stirring the mixture for 3-5 min, and then removing by
aspiration as much of the wash solution as possible. Similarly,
the resin was washed sequentially with DMF (200 mL),
methanol (2 × 200 mL), THF (2 × 200 mL), and methanol
Cr u d e Ald eh yd es
(
200 mL). A portion of the resin was removed for analysis: IR
-
l
1
734 cm (CdO).
To the resin remaining in the reactor was added THF (400
mL) and a 40% aqueous solution of methylamine (200 mL; 2.31
mol). This reaction mixture was stirred gently at 40 °C for 2
h and then cooled to room temperature (the mixture may be
held overnight at this temperature). As much of the reaction
liquor as possible was removed by aspiration, and the resin
was washed with the solvent array as above. Following the
final methanol wash, additional methanol was used to flush
the resin out of the bottom of the reactor and isolate it by
filtration. The filtered resin was dried at 40 °C under vacuum.
Yield 18-18.5 g resin: amine load 1.02 mequiv/g (based on
potentiometric titration of a THF suspension with p-toluene-
-
l
2
sulfonic acid); IR (microscopy) 3316 cm (w, -NH ). Anal.
found C, 87.07; H, 7.77; N, 1.58, which corresponds to 1.13
nitrogen atoms/g resin.
P r ep a r a tion of 4-Nitr op h en yleth a n eh yd r oxa m ic Acid .
A 200 mg sample of the dried resin (ca. 0.2 mmol) was charged
to a 5- or l0-mL resin reactor (a polypropylene syringe barrel
fitted with a polypropylene frit). The resin was swelled for
about 15 min in dry DMF (4 mL), and then EDCI (115 mg;
0
4
.6 mmol) was added. To this mixture was then added
-nitrophenylacetic acid (l15 mg, 0.6 mmol). The reactor was
capped, and the mixture was agitated slowly overnight (a
rocker bed apparatus was used). The reaction liquors were
removed by vacuum filtration, and the resin was washed by
several small (2-3 mL) portions of the following solvents:
DMF (four to five portions), 50% aqueous DMF (three to four
portions), THF (three to four portions), and MeOH (two to
three portions). The resin was dried for 4 h under vacuum at
40 °C. To this dried resin was added DCM (2 mL) followed by
TFA (2 mL containing 20 µL of water). The mixture was
allowed to react for about 1 h, and the reaction liquors were
drained into a tared collector. The resin was washed with DCM
a
Purity estimated by HPLC (A% at UV220).
Sch em e 5
(
2 × l mL) followed by toluene (2 × 1 mL). The combined
filtrates were concentrated to about 2 mL at 30 °C, additional
toluene (2 mL) was added, and the resulting solution was
concentrated to dryness under vacuum at 30 °C. The residue
was weighed and analyzed for weight % purity (HPLC, using
the carboxylic acid as a response factor standard). Typical
Ta ble 4. Keton es Obta in ed by Rea ction w ith Gr ign a r d
Rea gen ts
results for 4-nitrophenylhydroxamic acid: 29-30 mg solids at
1
60-70 wt % purity, 90-97 A% purity (261 nm); H NMR (CD
3
-
0
2
D) δ 8.13 (d, 2H), 7.25 (d, 2H), 4.85 (bs, OH, NH), 3.55 (s,
H); 13C NMR δ 169.4, 144.3, 131.3, 124.6, 40.2. This reflects
a chemical yield of 50-55% assuming resin loading at 1
mequiv/g.
3
,4-Dim eth oxycin n a m ic Ald eh yd e (7a ). A glass-jacketed
reaction vessel fitted with a porous glass frit was charged with
dry 4-O-(methylhydroxylamine)phenoxymethylcopoly(styrene-
1
%-divinylbenzene)resin (3) (1.02 g, 1 mmol, 1.02 mmol/g) and
then washed with DMF (15 mL) and suspended in DMF (15
mL). 3,4-Dimethoxycinnamic acid (624.6 mg, 3 mmol) and
EDCI (575.1 mg, 3 mmol) were added. The reaction mixture
was then shaken for 16 h at room temperature. The reaction
vessel was drained, washed with DMF (2 × 15 mL), 20%
aqueous THF (3 × 15 mL), THF (3 × 15 mL), and DCM (3 ×
a
Purity was estimated by GC analysis and 1H NMR.
1
5 mL), and dried in vacuo overnight. The dry resin was
stirred gently for about 15 min, and then as much solvent as
possible was removed through a tube fitted with a porous glass
frit via vacuum aspiration. Fresh THF (450 mL) was added,
followed by triphenylphosphine (15.74 g; 60 mmol) and N-
hydroxyphthalimide (16.31 g; 100 mmol). The resulting mix-
ture was stirred and cooled to 0 °C. Diisopropylazodicarbox-
ylate (11.8 mL; 60 mmol) is added slowly so as to maintain
shaken in anhydrous toluene (15 mL) for 10 min, DBU (0.9
mL, 6 mmol) was added, and the reaction mixture was shaken
for 2 h at room temperature. 4-Bromobenzyl bromide (1.5 g, 6
mmol) was added to the mixture, and the reaction vessel was
gently agitated for 3 days at room temperature. The reaction
vessel was drained, washed with DMF (3 × 15 mL), THF (3 ×
15 mL), DCM (3 × 15 mL), and dried in vacuo overnight. The

1
828 J . Org. Chem., Vol. 64, No. 6, 1999
Salvino et al.
dry resin was swelled in anhydrous THF (12 mL) under
nitrogen, shaken for 10 min, and cooled to 0 °C for 30 min.
Then LAH (1M in THF; 0.5 mL, 0.5 mmol) was added, and
the reaction vessel was shaken at 0 °C for 30 min. Then
The dry resin was swelled in anhydrous THF (12 mL) under
nitrogen, shaken for 10 min, and cooled to 0 °C for 30 min.
LAH (1 M in THF; 0.75 mL; 0.75 mmol) was added to the
reaction vessel at 0 °C and gently agitated for 30 min. Then
saturated KHSO
4
(0.5 mL) and K, Na tartrate (0.3 mL)
4
saturated KHSO (0.5 mL) and K, Na tartrate (0.3 mL)
solutions were added, and the reaction mixture was gently
agitated for 20 min while being warmed to room temperature.
solutions were added, and the reaction mixture was shaken
for 20 min while being warmed to room temperature. Anhy-
Excess water was dried by addition of anhydrous Na
mixture was filtered under low nitrogen pressure and washed
with DCM (3 × 8 mL). The filtrate was further dried with Na
SO (ca. 500 mg) and filtered through a short (1 in.) bed of
2
SO
4
. The
2 4
drous Na SO (ca. 500 mg) was added to the reaction mixture,
and the mixture was shaken for 15 min. The mixture was
filtered under low nitrogen pressure and washed with DCM
2
-
4
(3 × 10 mL). The filtrate was further dried with Na
2 4
SO and
silica gel 60 for column chromatography (particle size 0.040-
filtered with DCM (2 × 10 mL) through a short (1 in.) bed of
silica gel 60 for column chromatography (particle size 0.040-
0.063 mm). Concentration in vacuo afforded 44 mg (25% yield)
0
1
7
1
1
.063 mm). The column was rinsed afterward with DCM (1 ×
0 mL). Concentration in vacuo afforded 94 mg (49% yield) of
1
1
a : H NMR δ 9.65 (d, 1H), 7.40 (d, 1H), 7.12 (d, 1H), 7.06 (s,
of 7q: H NMR δ 9.56 (s, 1H), 5.10 (brs, 1H), 4.22 (q, 1H),
+
H), 6.87 (d, 1H), 6.60 (dd, 1H), 3.90 (s, 6H); MS (EI) m/z )
1.45 (m, 9H), 1.34 (d, 3H); MS (IS) m/z ) 173 [M ]. Purity
+
1
93 [M + H] LC area (UV220) ) 85%.
was estimated to be 90% by H NMR.
The following examples were synthesized following the
The following examples were synthesized following the
above procedure:
above procedure:
-P h en ylbu tyr a ld eh yd e (7b): 40 mg (27% yield); H NMR
δ 9.75 (s, 1H), 7.05-7.30 (m, 5H), 2.58-2.68 (m, 2H), 2.41-
.50 (t, 2H), 1.91-2.02 (m, 2H); MS (EI) m/z ) 149 [M + H]+
LC area (UV220) ) 90%.
-Aceta m id oben za ld eh yd e (7c): 30 mg (18% yield); H
NMR δ 9.98 (s, 1H), 7.97 (s, 1H), 7.86 (d, 1H), 7.62 (d, 1H),
1
4
N-r-(ter t-Bu toxyca r bon yl)-L-va lin a l (7r ): 22 mg (11%
1
yield); H NMR δ 9.61 (s, 1H), 5.09 (brs, 1H), 4.27 (m, 1H),
2
1.80 (brm, 1H), 1.48 (m, 9H), 1.03 (d, 3H), 0.95 (d, 3H); MS
+
1
(IS) m/z ) 201 [M ]. Purity was estimated to be 90% by H
1
3
NMR.
N-r-(ter t-Bu toxyca r bon yl)-L-p h en yla la n in a l (7s): 77 mg
+
7
.48 (t, 1H), 2.21 (s, 3H); MS (EI) m/z ) 164 [M + H] LC
1
(
(
34% yield); H NMR δ 9.62 (s, 1H), 7.12-7.34 (m, 5H), 5.04
area (UV220) ) 93%.
brs, 1H), 4.42 (t, 1H), 3.09 (d, 2H), 1.39 (s, 9H); MS (IS) m/z
1
+
2
-Biben zyla ld eh yd e (7d ): 76 mg (36% yield); H NMR δ
) 250 [M + H] LC area (UV220) ) 91%.
1
2
8
0.18 (s, 1H), 7.83 (d, 1H), 7.14-7.52 (m, 8H), 3.30 (t, 2H),
.87 (t, 2H); MS (EI) m/z ) 211 [M + H] LC area (UV220) )
N -r-(t er t -Bu t oxyca r b on yl)-â-(t er t -b u t yl)-L-a sp a r t a l
+
1
(
1
7t): 57 mg (21% yield); H NMR δ 9.63 (s, 1H), 5.60 (brs,
6%.
H), 2.82 (m, 2H), 2.02 (m, 1H), 1.42 (m, 18H); MS (IS) m/z )
4
-(4-n -P r op ylp h en yl)ben za ld eh yd e (7e): 98 mg (44%
274 [M + H] LC area (UV2 ) ) 80%.
+
20
1
yield); H NMR δ 10.02 (s, 1H), 7.92 (d, 2H), 7.72 (d, 2H), 7.53
N-r-(ter t-Bu toxyca r bon yl)-N-E-(ter t-bu toxyca r bon yl)-
(
2
d, 2H), 2.65 (t, 2H), 1.68 (dt, 2H), 0.95 (t, 3H); MS (EI) m/z )
1
L-lysin a l-OH (7u ): 63 mg (19% yield); H NMR δ 9.53 (s, 1H),
+
25 [M + H] LC area (UV220) ) 97%.
-Br om o-3-m eth ylben za ld eh yd e (7f): 60 mg (30% yield);
5
.21 (brs, 1H), 3.12 (m, 2H), 1.88 (m, 2H), 1.18-1.66 (m, 22H);
4
+
MS (IS) m/z ) 331 [M + H] LC area (UV220) ) 67%.
1
H NMR δ 9.94 (s, 1H), 7.70 (d, 2H), 7.52 (d, 1H), 2.45 (s, 3H);
1
2
-F or m ylin d ole (7r ): 41 mg (33% yield); H NMR δ 9.82
+
MS (EI) m/z ) 198/200 [M + H] LC area (UV220) ) 93%.
+
(
(
s, 1H), 7.14-7.75 (m, 6H); MS (EI) m/z ) 145 [M ] LC area
1
4
-Meth oxy-2-for m ylqu in olin e (7g): 27 mg (14% yield); H
UV254) ) 90%.
NMR δ 10.17 (s, 1H), 8.27 (d, 1H), 8.18 (d, 1H), 7.78 (t, 1H),
N -Be n zyl-4-O-(m e t h ylh yd r oxyla m in e )p h e n oxym e -
7
+
.62 (t, 1H), 7.38 (s, 1H), 4.12 (s, 3H); MS (EI) m/z ) 188 [M
th ylcop oly(styr en e-1%-d ivin ylben zen e)r esin (13). 4-O-
Methylhydroxylamine)phenoxymethylcopoly(styrene-1%-di-
+
H] LC area (UV220) ) 86%.
(
1
3
-F or m ylqu in olin e (7h ): 41 mg (26% yield); H NMR δ
vinylbenzene)resin (3) (2 g; 2 mmol) was swelled in DCM (15
mL) for 10 min, DIEA (0.383 mL; 2.2 mmol) was added, and
the reaction mixture was shaken for 1 h at room temperature.
Then allyl chloroformate (0.234 mL; 2.2 mmol) was added, and
the reaction mixture was shaken overnight at room temper-
ature. The resin was filtered, washed with DCM (3 × 15 mL),
THF (3 × 15 mL), and DCM (3 × 15 mL), and dried in vacuo.
Dry resin (11) was swelled in anhydrous toluene (18 mL), and
then DBU (1.5 mL; 10 mmol) was added and shaken for 1 h
at room temperature. Finally benzyl bromide (1.19 mL; 10
mmol) was added, and the reaction mixture was shaken for 3
days at room temperature. The reaction vessel was drained
and the resin was washed with DCM (3 × 15 mL), DMF (3 ×
15 mL), THF (3 × 15 mL), and DCM (3 × 15 mL), and dried
overnight in vacuo. To the resin were added THF (6 mL),
DMSO (6 mL), 0.5 N HCl (2.5 mL), tetrakis(triphenylphos-
phine) palladium(0) (347 mg; 15 mol %), and morpholine (4.3
mL), and the reaction mixture was shaken overnight at room
temperature. The resin was then drained, washed with DMF
(3 × 15 mL), THF (3 × 15 mL), DCM (3 × 15 mL), 0.5%
aqueous HCl in DCM (3 × 15 mL), 0.5% sodium diethyldithio-
carbamate in DMF (3 × 15 mL), DMF (3 × 15 mL), THF (3 ×
15 mL), and DCM (3 × 15 mL), and then dried in vacuo. A
resin sample (13) (100 mg; 0.1 mmol) was cleaved with 50%
TFA in DCM (2 mL) for 1 h at room temperature, washed 2×
with 1 mL of the cleavage mixture, evaporated, and dried in
vacuo to give N-benzylhydroxylamine (10 mg; 0.081 mmol;
1
1
0.26 (s, 1H), 9.38 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 7.98 (t,
+
H), 7.89 (t, 1H), 7.65 (t, 1H); MS (EI) m/z ) 158 [M + H] LC
area (UV220) ) 94%.
2
-(Meth ylth io)n icotin ic a ld eh yd e (7i): 48 mg (31% yield);
1
H NMR δ 10.21 (s, 1H), 8.60 (d, 1H), 7.98 (d, 1H), 7.15 (dd,
+
1
)
H), 2.60 (s, 3H); MS (IS) m/z ) 154 [M + H] LC area (UV220)
98%.
N-P h en yla n th r a n ilic a ld eh yd e (7j): 92 mg (47% yield);
1
H NMR δ 9.88 (s, 1H), 7,52-7.58 (d, 1H), 7.11-7.38 (m, 7H),
+
6
8
.81 (t, 1H); MS (EI) m/z ) 198 [M + H] LC area (UV220) )
9%.
1
2
-P h en yl-4-for m ylqu in olin e (7k ): 62 mg (27% yield); H
NMR δ 10.58 (s, 1H), 9.00 (d, 1H) 8.19-8.30 (m, 4H), 7.82 (t,
1
H), 7.70 (t, 1H), 7.47-7.59 (m, 3H);. MS (EI) m/z ) 234 [M +
+
H] LC area (UV220) ) 90%.
Ben zo(â)th iop h en e-2-a ld eh yd e (7l): 76 mg (46% yield);
1
H NMR δ 10.12 (s, 1H), 8.03 (s, 1H), 7.93 (m, 2H), 7.47 (m,
+
2
H); MS (EI) m/z ) 162 [M ] LC area (UV220) ) 87%.
3
-(3,4-Met h ylen ed ioxy)p r op ion a ld eh yd e (7m ): 97 mg
1
(
(
54% yield); HNMR δ 9.80 (s, 1H), 7.60-7.74 (m, 3H), 5.92
+
s, 2H), 2.88 (t, 2H), 2.74 (t, 2H); MS (EI) m/z ) 179 [M + H]
LC area (UV220) ) 95%.
N-r-(ter t-Bu toxyca r bon yl)-L-a la n in a l (7q): N-benzyl-4-
O-(methylhydroxylamine)phenoxymethylcopoly(styrene-1%-di-
vinylbenzene)resin (13) (1.08 g; 1 mmol) was washed with
DMF (15 mL) and then suspended in DMF (15 mL). Boc-Ala-
OH (568 mg; 3 mmol) and EDCI (575.1 mg; 3 mmol) were
added, and the reaction mixture was shaken for 16 h. The
reaction vessel was drained, and the resin was washed with
DMF (2 × 15 mL), 20% aqueous THF (3 × 15 mL), THF (3 ×
81%): 1H NMR (CD
OD) δ 7.44 (m, 5H), 4.36 (s, 2H); MS (EI)
3
+
m/z ) 124 [M + H] .
4-O -(B e n z y ld i e t h y lp h o s p h o n o a c e t a t e )p h e n o x y -
m et h ylcop oly(st yr en e-1%-d ivin ylb en zen e)r esin (16a ).
Wang resin (Advanced Chem Tech; 40 g; 1.09 mmol/g loading;
1
5 mL), and DCM (3 × 15 mL) and dried in vacuo overnight.

Synthesis of Aldehydes, Ketones, and Hydroxamic Acids
3.6 mmol) was placed in a 2 L three-neck round-bottom flask
J . Org. Chem., Vol. 64, No. 6, 1999 1829
4
at 40 °C to give N-4-phenylbut-l-oyl-4-O-(methylhydroxylami-
and swelled with DMF (400 mL) for 20 min. An overhead
stirrer was attached to provide gentle stirring. Added in
succession were diethylphosphonoacetic acid (21 mL; 130.8
mmol), anhydrous pyridine (22 mL; 261.6 mmol), and 2,6-
dichlorobenzoyl chloride (19 mL, 130.8 mmol) at room tem-
perature. The solution was stirred at ambient temperature for
ne)phenoxymethylcopoly(styrene-l%-divinylbenzene)resin (2.2
g): IR CdO 1670 cm . Anal. Calcd: N, 1.05. Found: N, 1.07.
-
l
N-4-Phenylbut-l-oyl-4-O-(Methylhydroxylamine)phenoxym-
ethylcopoly(styrene-1%-divinylbenzene)resin (1.46 g; 1.095
mmol) was suspended in toluene (26 mL) for 10 min. DBU
(0.83 mL; 5.5 mmol) was added, and the mixture was agitated
1
2 h, during which time the reaction mixture turned an orange
for 2 h on a wrist shaker. 4-Bromobenzyl bromide (4.1 g; 16.425
mmol) was added, and the reaction mixture was vigorously
agitated for 4 days. The resin was filtered, washed with DMF
color. The resin was then filtered and washed with DMF, THF,
DCM, and MeOH. Each wash solvent addition was ap-
proximately 400 mL, and each washing step was repeated five
to eight times. The resin was dried in vacuo overnight at 25
(
3 × 50 mL), 20% aqueous DMF (3 × 50 mL), DMF (3 × 50
mL), THF (3 × 50 mL), and Et O (3 × 50 mL), and dried under
2
-
1
°
C: IR CdO 1737 cm
.
vacuum at 40 °C to give N-4-bromobenzyl-N-4-phenylbut-l-
4
-O-(Ben zyld iet h ylp h osp h on op r op ion a t e)p h en oxy-
ylcarbonyl-4-O-(methylhydroxylamine)phenoxymethylcopoly-
m eth ylcopoly(styr en e-1%-divin ylben zen e)r esin (16b). 16b
was prepared in a method similar to that of 16a following the
above procedure from diethyl-2-phosphonopropionic acid: IR
-l
(styrene-1%-divinylbenzene)resin (1.4 g): IR CdO 1668 cm
.
Anal. Calcd: Br, 5.3; N, 0.94. Found: Br, 5.4; N, 0.85.
N-4-Bromobenzyl-N-4-phenylbut-1-oyl-4-O-(methylhydroxy-
lamine)phenoxymethylcopoly(styrene-l %-divinylbenzene)resin
-
1
CdO 1733 cm
.
5
-(3,4-Dim eth oxyp h en yl)p en ta -2,4-d ien oic Acid (17a ).
[0.15 g (ca. 0.75 mmol/g); 0.11 mmol] was suspended in diethyl
Resin 16a (100 mg; 0.063 mmol) was swelled in dry THF (1.5
mL) for 15 min at room temperature and then cooled under
nitrogen to 0 °C for 15 min. LiHMDS (1 M in hexane; 0.16
mL; 0.16 mmol) was added and the reaction mixture brought
to room temperature over 30 min. The reaction was filtered
under an inert nitrogen atmosphere, and then cyclohexane (1.2
mL) was added to the reaction vessel followed by the addition
of 3,4-dimethoxycinnamic aldehyde (7a ) (29 mg; 0.15 mmol)
in 0.3 mL of THF. The mixture was shaken for 16 h on an
orbital shaker under nitrogen. The resin was subsequently
washed with DMF (3 × 3 mL), 20% aqueous THF (3 × 3 mL),
ether (1 mL) and treated with ethylmagnesium bromide (1 M
in THF) (0.34 mL, 0.34 mmol). The reaction mixture was
agitated for 18 h and then quenched by the addition of 2 M
HCl (aqueous) (approximately pH 3 is obtained). The mixture
was agitated for 30 min. Sodium sulfate was added, and the
mixture was filtered through a plug of silica gel, washed
thoroughly with DCM, and concentrated to give of 6-phenyl-
hexan-3-one (13 mg; 0.0748 mmol; 68%): GC MS (EI) area )
+
+ 1
9
7.1%, m/z 176.2 (M) ; MS (EI-LRP) m/z 176 (M) ; H NMR
300 MHz, CDCl ) δ 1.02 (t, 3H), 1.9 (m, 2H), 2.4 (m, 4H) 2.6
m, 2H), 7.2-7.3 (m, 5H).
-(4-Br om o-3-m eth ylp h en yl)p r op a n -l-on e (18b). Dry
-O-(methylhydroxylamine)phenoxymethylcopoly(styrene-1%-
(
(
3
THF (3 × 3 mL), DCM (2 × 3 mL), THF (3 × 3 mL), and Et
2
O
1
(2 × 3 mL) and dried in vacuo. The resin was cleaved with
4
5
0% TFA in DCM (3 mL) for 2 h at room temperature and
divinylbenzene)resin (3) (4 g; 3 mmol) was allowed to swell in
DMF (32 mL) for 10 min and then was treated with 4-bromo-
3-methylbenzoic acid (1.93 g; 9 mmol) and EDCI (1.725 g; 9
mmol). The mixture was shaken for 24 h and filtered. The resin
was washed with DMF (3 × 50 mL), 20% aqueous DMF (3 ×
washed with the cleavage solution (3 × 1 mL), and the washes
were combined and evaporated. Drying overnight in vacuo
1
gave 12 mg (81% yield) of 17a : H NMR (CD
1
(
3
OD) δ 7.52 (m,
H), 6.98-7.08 (m, 2H), 6.69-6.91 (m, 3H), 5.93 (d, 1H), 3.92
s, 3H), 3.90 (s, 3H); MS (EI) m/z ) 234 [M + H] LC area
+
5
5
3
0 mL), DMF (3 × 50 mL), THF (3 × 50 mL), and Et2O (3 ×
0 mL) and dried under vacuum at 40 °C to give N-(4-bromo-
-methylbenzoyl)-4-O-(methylhydroxylamine)phenoxyme-
(UV220) ) 99%.
The following examples were synthesized following the
above procedure:
-(3,4-Dim eth oxyph en yl)-2-eth ylpen ta-2,4-dien oic Acid
17b): Resin 16b and 7a afforded 5.5 mg (33% yield) of 17b:
thylcopoly(styrene 1%-divinylbenzene)resin (4.5 g): IR CdO
5
-
1
1
677 cm . Anal. Calcd: Br, 5.2; N, 1.05. Found: Br, 5.3; N,
0.91.
Clea va ge fr om Resin To Con fir m Loa d in g. N-(4-Bromo-
(
1
H NMR (CD
3
OD) δ 7.41 (d, 1H), 6.65-7.13 (m, 6H), 3.93 (s,
3
[
H), 3.90 (s, 3H), 2.52 (q, 2H), 1.12 (t, 3H); MS (EI) m/z ) 262
+
3-methylbenzoyl)-4-O-(methylhydroxylamine)phenoxyme-
thylcopoly(styrene-1%-divinylbenzene)resin (100 mg; 0.075
mmol) was suspended in 50% TFA/CH Cl for 2 h. The resin
2 2
was filtered and washed three times with DCM and then
M + H ] LC area (UV220) ) 97%.
-(4-Br om o-3-m eth ylp h en yl)a cr ylic Acid (17c). Resin
6a and 4-bromo-3-methyl benzaldehyde (7f) gave 11 mg (72%
3
1
1
yield) of 17c: H NMR (CD
1
H] LC area (UV220) ) 91%.
-(4-Br om o-3-m eth ylp h en yl)-2-eth yla cr ylic a cid (17d ).
3
OD) δ 7.48-7.66 (m, 3H), 7.30 (d,
concentrated to give N-hydroxy-4-bromo-3-methylbenzamide
H), 6.45 (d, 1H), 2,37 (s, 3H); MS (EI) m/z ) 240/242 [M +
+
+
(17.2 mg; 0.075 mmol): LC MS m/z 230/232 (Br) [M + H]
1
area ) 78%; H NMR δ 2.42 (s, 3H), 7.4 (bd J ) 7.89, 1H),
3
1
7.58 (bd J ) 7.89, 1H), 7.62 (bs, 1H).
Resin 16b and 7f afforded 11.5 mg (68% yield) of 17d : H NMR
CD OD) δ 7.68 (s, 1H), 7.21-7.31 (m, 5H), 6.91-7.12 (m, 4H),
.44-2.52 (q, 2H), 1.18 (t, 3H); MS (EI) m/z ) 268/270 [M +
(
2
3
N-(4-Bromo-3-methylbenzoyl)-4-O-(methylhydroxylamine)-
phenoxymethylcopoly(styrene-1%-divinylbenzene)resin (2.8 g;
2.1 mmol) was suspended in toluene (27 mL), and the mixture
was stirred for 10 min. DBU (1.6 g; 10.5 mmol) was added,
and the mixture was agitated for 2 h on a wrist shaker.
4-Chlorobenzyl bromide (6.47 g; 31.5 mmol) was added, and
the reaction mixture was vigorously agitated for 3 days. The
resin was filtered, washed with DMF (3 × 30 mL), 20%
aqueous DMF (3 × 30 mL), DMF (3 × 30 mL), THF (3 × 30
mL), and Et2O (3 × 30 mL), and dried under vacuum at 40
+
H ] LC area (UV220) ) 92%.
-(2-P h en yla m in op h en yl)a cr ylic Acid (17e). Resin 16a
and N-phenylanthranilic aldehyde (7j) gave 10 mg (82% yield)
of 17e: H NMR (CD
7
2
3
1
3
OD) δ 8.05 (d, 1H), 7.56 (d, 1H), 7.18-
.31 (m, 4H), 6.87-7.02 (m, 4H), 6.39 (d, 1H); MS (EI) m/z )
+
39 [M + H] LC area (UV220) ) 89%.
-E t h yl-3-(2-p h en yla m in op h en yl)a cr ylic a cid (17f).
2
1
Resin 16b and 7j afforded 5.2 mg (31% yield) of 17f: H NMR
CD OD) δ 7.78 (s, 1H), 7.21-7.31 (m, 5H), 6.91-7.12 (m, 4H)
.44-2.52 (q, 2H). 1.18 (t, 3H); MS (EI) m/z ) 267 [M + H ]
LC area (UV220) ) 96%.
-P h en ylh exa n -3-on e (18a ). Dry 4-O-(methylhydroxy-
°
C to give N-4-chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-
(
2
3
+
O-(methylhydroxylamine)phenoxymethylcopoly(styrene-1%-di-
-
1
vinylbenzene)resin (3g): IR CdO 1644 cm . Anal. calcd: Br,
4
.2; Cl, 1.9; N, 0.8. Found: Br, 3.8; Cl, 2.0; N, 0.9.
6
lamine)phenoxymethylcopoly(styrene-1%-divinylbenzene)res-
N-4-Chlorobenzyl-N-(4-bromo-3-methylbenzoyl)-4-O-(meth-
in (3) (2 g, 1.5 mmol) was allowed to swell in DMF (8 mL) for
ylhydroxylamine)phenoxymethylcopoly(styrene-l%-divinylben-
zene)resin [0.23 g (ca. 0.5 mmol/g); 0.115 mmol] was suspended
in diethyl ether (1 mL) and treated with ethylmagnesium
bromide (1.0 M in THF, 0.23 mL; 0.23 mmol). The reaction
mixture was agitated for 18 h, and then quenched by the
addition of 2 M HCl (aqueous) (pH ∼3 is obtained). The
1
0 min and then was treated with 4-phenylbutyric acid and
EDCI (0.86 g, 4.5 mmol). The mixture was shaken for 24 h
and filtered. The resin was washed with DMF (3 × 50 mL),
2
5
0% aqueous DMF (3 × 50 mL), DMF (3 × 50 mL), THF (3 ×
2
0 mL), and Et
O (3 × 50 mL) and then dried under vacuum

1
830 J . Org. Chem., Vol. 64, No. 6, 1999
Salvino et al.
mixture was agitated for 30 min. Sodium sulfate was added,
and the mixture was filtered through a plug of silica gel,
rinsing with DCM (2 × 20 mL). The residue was concentrated
to give 1-(4-bromo-3-methylphenyl)propan-l-one (6.0 mg; 0.026
Ack n ow led gm en t. Thanks to Drs. S. Tang and B.
Hsu for mass spectra and analytical expertise. Thanks
to Dr. G. McGeehan for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and mass
spectra for compounds 7a -m ,q-v and 17a -f.
+
mmol; 23%): GC area ) 78.7%; MS (EI) m/z 226 Br [M - H];
1
H NMR δ 1.22 (t, J ) 7.89, 3H), 2.96 (q, J ) 7.89, 2H), 7.6
(bs, 2H), 7.8 (s, 1H).
J O981431R