Application of a new solid-phase resin: Benzamide ortho-lithiation and the synthesis of a phthalide library

Article abstract of DOI:10.1055/s-1999-2863

The utility of new polytetrahydrofuran cross-linked polystyrene resins is demonstrated through the solid-phase synthesis of a phthalide library. The phthalides are synthesized via directed ortho-lithiation of resin bound benzamides and isolated via cyclat

Full text of DOI:10.1055/s-1999-2863

1
438
LETTER
Application of a New Solid-Phase Resin: Benzamide ortho-Lithiation and the
Synthesis of a Phthalide Library
a
b
a
b,*
Patrick Garibay, Patrick H. Toy, Thomas Hoeg-Jensen , Kim D. Janda
aNovo Nordisk A/S, Novo Alle 6BS.58, DK-2800 Bagsvaerd, Denmark
bDepartment of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road,
La Jolla, CA 92037
Received 6 July 1999
more “organic solvent-like” than that of divinyl benzene
Abstract: The utility of new polytetrahydrofuran cross-linked poly-
(
DVB) cross-linked resins. (2) Anticipation that the flexi-
styrene resins is demonstrated through the solid-phase synthesis of
a phthalide library. The phthalides are synthesized via directed
ortho-lithiation of resin bound benzamides and isolated via cycla-
tive cleavage.
ble PTHF cross-linkers could result in better site accessi-
bility as compared to relatively rigid DVB cross-linked
resins. Herein we report the utilization of the PTHF cross-
linked resins in the synthesis of a phthalide library via a
benzamide ortho-lithiation reaction.
Key words: solid-phase synthesis, resin, ortho-lithiation, phthalide
The synthetic utility of the directed ortho-metallation
1
(
DoM) reaction is well documented. Despite the renewed
interest in the adaptation of solution-phase organic reac-
tions to the solid-phase, there are only two reported ex-
1a: n = 1
1
b: n = 3.5
2
1c: n = 9.5
amples of DoM chemistry applied on a solid support: (1)
3
The lithiation of 1-hydroxyimidazole with n-BuLi. In this
O
O
n
case, the increased acidity of the proton on the heterocycle
allowed for selective deprotonation without interference
4,5
Figure 2 Polytetrahydrofuran-based resin cross-linkers.
caused by resin deprotonation, which is known to occur.
(
2) A single example of the lithiation of a phenyl ether.6
The development of a general procedure for the solid-
phase DoM of the commonly used benzamide moiety
would greatly extend the utility of this type of chemistry.
Furthermore, the directed lithiation of benzamides could
provide convenient access to the phthalide class of com-
pounds (Figure 1). Using such a strategy, the solid-phase
DoM of benzamides to synthesize a library of phthalide
molecules would have two noteworthy features: (1) The
trapping step is amenable to the use of a variety of electro-
philes. (2) The amide functionality acts as both the direct-
ing group for metalation and as the linker to the resin. The
result of this combination is that cyclic cleavage of only
the desired product would be observed.
Traditionally aminomethyl resins are prepared by deriva-
tization of preformed resin beads. We chose an alterna-
8
tive method that involves the incorporation of a
functionalized monomer into the polymerization reaction.
It was deemed that this procedure would result in resins of
more highly defined composition. Thus, aminomethyl
resins 2a-c were prepared by suspension copolymeriza-
tion of 1a-c, 3 and styrene followed by removal of the ph-
thalimide protecting group (Figure 3). We believe that in
the future this process of polymerization of functional
monomers will become a valuable alternative to tradition-
7
al bead derivitization. As previously reported, we found
that for resins cross-linked with 1a-c, at least 5 mole per-
cent cross-linking was required to ensure resin stability to
n-BuLi. Therefore resins 2a-c are all 5 percent cross-
linked. It should be noted that incorporation of 3 into the
polymerization process allowed for direct attachment of
the requisite aroyl molecule to the resin without use of an
intermediary spacer or linker group.
O
O
R
Ar
Figure 1 General structure of phthalide library compounds.
Resins 2a-c were treated with benzoyl chloride and trieth-
yl amine to yield 4a-c. Sequential treatment of 4a-c with
tetramethylethylene diamine (TMEDA) and sec-BuLi
was followed by addition of 4-anisaldehyde. Product 5
was obtained by treatment of the resins with refluxing tol-
uene (Table 1). It should be noted that commercial DVB
cross-linked polystyrene (PS) provided lower yield than
We have recently introduced a new class of resins de-
signed specifically for solid-phase organic synthesis that
are based on polytetrahydrofuran (PTHF) cross-linkers
7
1
a-c (Figure 2). Our decision for utilizing this type of
cross-linking element was based upon the following con-
siderations: (1) The desire to create a resin interior that is
did resins 2a-c. Tentagel-NH was also examined, but
2
only trace amounts of contaminated 5 could be isolated.
Synlett 1999, No. 9, 1438–1440 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Benzamide ortho-Lithiation and the Synthesis of a Phthalide Library
1439
O
A: R = H
N
B: R = OMe
C: R = CF3
O
H
R
+
KN
O
Figure 5 Benzamide components for library synthesis.
N
O
Cl
O
In conclusion, a general method for the solid-phase DoM
of benzamides has been developed and its versatility has
been demonstrated through the generation of a high purity
phthalide library. Furthermore, our new PTHF cross-
linked resins have been shown to be suitable supports for
this chemistry and they provide improved results com-
pared to some of the most broadly used commercially
available resins.
3
1
. suspension
polymerization
. H2NNH2
3
+ styrene + 1a, 1b or 1c
2
NH2
2a-c
Figure 3 The preparation of phthalimide monomer 3 and amino-
methyl resins 2a-c.
Experimental
9
N-(4-vinylbenzyl)phthalimide (3). A solution of 4-vinylbenzyl
O
chloride (25.0 mL, 160 mmol), and potassium phthalimide (31.0 g,
168 mmol) in DMF (175 mL) was stirred at 60 °C for 16 h. The sol-
vent was removed in vacuo and the resulting solid material was. and
the resulting solid material was dissolved in CH Cl (250 ml). The
1
. sec-BuLi, TMEDA
Ph or n-BuLi
. 4-anisaldehyde
NH2 BzCl, Et3N
N
H
2
2
2
2a-c
4a-c
organic solution was washed sequentially with 0.2 M NaOH (2 x
00 mL), water (200 mL), dried over MgSO , filtered and concen-
2
4
O
OMe
trated in vacuo. The crude product was recrystallized from ethanol
1
to afford 3 (28.6 g, 68% yield), mp = 97-98 °C, H NMR (300 MHz,
O
HO
O
CDCl ): d 4.83 (s, 2H), 5.22 (d, J = 10.6 Hz, 1H), 5.70 (d, J = 17.5
3
refluxing toluene
Hz, 1H), 6.67 (dd, J = 17.5 Hz, J = 10.6 Hz, 1H), 7.33-7.42 (m,
1
2
N
H
4H), 7.67-7.86 (m, 4H).
General procedure for resin 2a-c synthesis.
MeO
5
A solution of acacia gum (6.0 g) and NaCl (3.75 g) in water (150
mL) was placed in a 150 mL flanged reaction vessel equipped with
Figure 4 The solid-phase synthesis of 5.
1
0
a floating magnetic stirrer and deoxygenated by purging with N .
2
A solution of 3 (2.00 g, 7.60 mmol), styrene (6.0 mL, 52.4 mmol),
1
c (2.65 g, 3.00 mmol), and benzoyl peroxide (0.15 g) in chloroben-
zene (9 mL) was injected into the rapidly stirred aqueous solution.
This mixture was heated to 85 °C for 16 h. The crude polymer was
collected and washed in a Soxhlet extractor with water, THF and
hexanes. The beads (8.52 g, 84%) were dried in vacuo and sieved to
afford resins in 3 size ranges: 50-100 mesh (1.48 g, 15%), 100-200
mesh (3.49 g, 35%) and 200-400 mesh (1.66 g, 16%). The 100-200
Table 1 Yields of the solid-phase synthesis of 5.
.
mesh resin was suspended in refluxing 95% EtOH/H NNH H O
2
2
2
(20:1, 40 mL) for 16 h. The resin was collected, washed with hot
EtOH, H O, dioxane, and MeOH (50 mL of each solvent) and dried
2
in vacuo. The amine loading level was determined by FMOC re-
1
1
lease assay.
Since resin 2c afforded the highest yield of 5, it was cho-
sen as the support for the library synthesis. During further
optimization of the reaction, it was found that higher
yields were obtained when n-BuLi was used in the ab-
sence of TMEDA. To generate a diverse library, resin 2c
was treated with benzoyl chloride, 4-methoxybenzoyl
chloride and 4-trifluoromethylbenzoyl chloride to afford
General procedure for benzamide resins A-C synthesis.
Resin 2c (1.0 g) was swollen in dry THF (15 mL) and treated with
triethyl amine (5 eq.) and benzoyl chloride (5 eq.). After 1 h at room
temperature, the resin was washed with THF, 1:1 THF/H O, DMF,
2
MeOH and ether (40 mL of each solvent) and dried in vacuo. Resins
12
A-C were negative to a Kaiser amine test.
resins A, B, and C, respectively (Figure 5). These three General procedure for phthalide library synthesis.
electronically different benzamides were lithiated with n- Resin A (0.126 mmol) was placed in a flame dried 50 mL round bot-
tom flask equipped with a nitrogen inlet and a magnetic stirrer. Dry
THF (10 mL) was added, the reaction mixture was cooled to 0 °C
BuLi and reacted each with 8 aromatic aldehydes to afford
a 24 member library (Table 2). All compounds were char-
1
and n-BuLi (7 eq., 2.5 M in hexanes) was added. After 5 min the al-
dehyde (10 eq.) was added and the reaction mixture was allowed to
stir at 0 °C for an additional 30 min. The reaction mixture was
warmed to room temperature and after 1 h the resin was washed
with THF, DMF, MeOH and ether (10 mL of each solvent). The re-
acterized by H-NMR and found to be greater than 95 per-
cent pure. Furthermore, yields were comparable to what is
observed in solution-phase chemistry.1
Synlett 1999, No. 9, 1438–1440 ISSN 0936-5214 © Thieme Stuttgart · New York

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440
P. Garibay et al.
LETTER
Table 2 Phthalide library yields
sulting resin was refluxed 16 h in toluene, filtered and the filtrate
was concentrated in vacuo to afford the phthalide in greater than
Benzamide
1
9
5% purity as determined by H NMR spectroscopy.
Aldehyde
A
B
C
O
Acknowledgement
H
64
50
73
This work was supported financially by the National Institutes of
Health (GM-56164), The Skaggs Institute for Chemical Biology
and The Scripps Research Institute. We thank BASF AG for the gift
of polytetrahydrofuran 250.
OMe
O
H
5
8
3
56
54
79
72
Me
References and Notes
O
(
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O
O
O
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437-2096,E;1999,0,09,1438,1440,ftx,en;S03799ST.pdf
Synlett 1999, No. 9, 1438–1440 ISSN 0936-5214 © Thieme Stuttgart · New York