1076 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
Sch em e 3
Sch em e 4
this type of 3CC reactions, 2′-formylphenoxy-2-benzoic
acid (7) was synthesized and tested in 3CC reactions. As
illustrated in Scheme 3, salicylaldehyde and ethyl 2-bro-
mobenzoate were coupled using a reported diaryl ether
synthesis procedure8 to give diaryl ether 6 in 24% yield.
Hydrolysis of ester 6 provided 2′-formylphenoxy-2-benzoic
acid in nearly quantitative yield. 2′-Formylphenoxy-2-
benzoic acid participates in a 3CC reaction to form a
heterocyclic structure that has an 8-membered lactam
ring (Scheme 2). For instance, 5a was prepared in 33%
yield by reacting 2′-formylphenoxy-2-benzoic acid with
4-(tert-butoxycarbonylamino)butylamine and methoxy-
ethyl isocyanide. The yields of the reactions of 2′-
formylphenoxy-2-benzoic acid with amines and isocya-
nides are relatively low, in the range of 20-40% (Table
1), presumably due to the difficulties of forming that
8-membered ring.
Exp er im en ta l Section
1H NMR spectra were recorded using 60 or 200 MHz NMR
spectrometers. Chemical shifts were referenced with TMS as the
internal standard. HPLC was run on a 0.4 × 10 cm C18 column
with 0.1% TFA water as buffer A and acetonitrile as buffer B.
Syn th esis of Com p ou n d 2a . To 2.0 g (13.3 mmol) of
2-formylbenzoic acid in 10 mL of methanol was added 2.5 g (13.3
mmol) of 4-(tert-butoxycarbonylamino)butylamine and 1.4 mL
(13.3 mmol) of tert-butyl isocyanide. The resulting solution was
stirred at room temperature overnight. TLC showed that the
reaction was complete after the incubation. Volatile solvent was
then removed in vacuo. The remaining residue was purified by
flash chromatography eluted with 1:1 hexane/ethyl acetate to
afford 4.6 g (87%) of the purified product. FAB-MS: found [M +
Besides those bifunctional reagents that are com-
mercially available, a variety of them can be synthesized
conveniently. For instance, the synthesis of 2-formylphen-
ylaceticacid,9a 3-formylindole-2-carboxylicacid,9b 2-formylin-
dole-3-acetic acid,9c 2′-formyldiphenyl-2-carboxylic acid9d
have been reported. In our laboratory, 2-formylphenoxy-
acetic acid derivatives were prepared (Scheme 4) using
substituted phenols. As shown in Scheme 4, phenols were
converted to salicylaldehyde derivatives by the Reimer-
Tiemann reaction.10 Alkylation of the salicylaldehyde
derivatives followed by saponification yielded bifunctional
compound 11, which then reacted with primary amines
and isocyanides to form substituted 1,4-benzoxazepin-3-
one-5-carboxamides (12). In structure 12, four indepen-
dent R groups were introduced through a series of
reactions, thus allowing rapid achievement of diversity.
1
H]+ ) 404, calcd [M + H]+ ) 404. H NMR (CDCl3): δ 7.67 (m,
4H), 5.85 (s, 1H), 4.95 (s, 1H), 3.20 (m, 4H), 1.58 (m, 4H), 1.43
(s, 9H), 1.29 (s, 9H).
Syn th esis of Com p ou n d 4a . To 0.5 g (2.78 mmol) of
2-formylphenoxyacetic acid in 5.0 mL of DMSO were added 0.28
g (2.78 mmol) of N-acetylethylenediamine in 5.0 mL of methanol
and 0.52 g (2.78 mmol) of ethyl 3-(2′-isocyanoethyl)thiopropi-
onate. The reaction solution was stirred at room temperature
overnight followed by removal of the volatile organic solvent in
vacuo. Then 20 mL of water was added to the remaining solution,
and the solution was extracted with 20 mL of ethyl acetate 5
times until no reaction product was left in the water layer. The
combined extract was dried with sodium sulfate and concen-
trated. Compound 4a was then purified on a silica flash column
eluted with 10:1 ethyl acetate/methanol to obtain 0.85 g (yield
In conclusion, by using bifunctional starting materials
that have aldehyde and carboxylic acid functional groups
in a 3CC reaction, unique lactam structures were pre-
pared. These new structures broaden the scaffolds that
are accessible through Ugi reactions, and many of them
may represent interesting pharmacophores. Further-
more, these 3CC reactions are amenable to solution-
phase as well as solid-phase combinatorial library syn-
thesis, thus allowing rapid synthesis of relevant small
molecule libraries.
is 70%). FAB-MS: found [M + H]+ ) 452, calcd [M + H]+
)
452. 1H NMR (CDCl3): δ 7.31 (m, 4H), 6.60 (t, 1H), 4.96-4.00
(m, 3H), 3.60 (s, 3H), 3.54-3.36 (m, 6H), 2.61 (m, 6H), 1.90 (s,
3H).
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and 1H NMR, IR, and MS spectra of phenylethyl
isocyanide, methoxyethyl isocyanide, methyl 3-(2′-isocyanoeth-
yl)thiopropionate, compound 1, 3, 5, 6, 7, 8, 9, 10, 11, and 12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 2. (b) J ung,
M. E.; Lazarova, T. I. J . Org. Chem. 1997, 62, 1553-1555.
J O982192A