'Michael-Michael-Wittig' reactions of (2,4-dioxobutylidene)phosphoranes with 3-formylchromones

Article abstract of DOI:10.1055/s-2003-37104

4-(2′-Hydroxybenzoyl)salicylic esters and amides were prepared by domino 'Michael-retro-Michael-Wittig' reactions of (2,4-dioxobutylidene)triphenylphosphoranes with 3-formylchromones.

Full text of DOI:10.1055/s-2003-37104

4
02
LETTER
‘
Michael–Michael–Wittig’ Reactions of (2,4-Dioxobutylidene)phosphoranes
with 3-Formylchromones
‘
P
Michael–Mic
e
hael–Wittig
t
’
Reac
e
tions of (2,4
r
-Dioxobutylid
L
ene)phosphoran
a
es nger,* Edith Holtz
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstrasse 16, 17487 Greifswald, Germany
E-mail: peter.langer@uni-greifswald.de
Received 5 January 2003
O
O
Abstract: 4-(2′-Hydroxybenzoyl)salicylic esters and amides were
prepared by domino ‘Michael–retro-Michael–Wittig’ reactions of
H
Ph P
3
O
O
OiPr
(
2,4-dioxobutylidene)triphenylphosphoranes
with
3-formyl-
3a
chromones.
O
O
O
NaH, THF
reflux
Key words: Michael–Michael–Wittig-reaction, 4-(2′-hydroxyben-
zoyl)salicylic esters, 4-(2′-hydroxybenzoyl)salicylic amides, (2,4-
dioxobutylidene)triphenylphosphoranes
O
H
H
+
58%
iPrO
O
4a
2a
Salicylic derivatives are of pharmacological relevance
and possess industrial applications. This includes natural
products, such as salicylic acid, various salicylic esters
and salicylic glycosides (e.g. salicortin), and synthetic
- Ph3P=O
O
O
O
O
O
H
O
PPh3
H
©
1
PPh3
O
compounds (e. g. aspirin ). In this context, the develop-
ment of new syntheses of (2′-hydroxybenzoyl)salicylic
esters is of considerable interest, since they represent
fragments and potential synthetic building blocks of a
variety of pharmacologically relevant natural products,
such as anthracyclines, pyoluteorin, pyrrolomycines,
O
OH
iPrO
iPrO
O
A
B
2
3
anthranoids and their analogues.
A number of classic syntheses of benzoylsalicylic deriva-
O
O
OLi OLi
OEt
Me SiO
OSiMe3
OEt
3
4
a
tives use Friedel–Crafts acylations. The regioselectivity
and yields of this approach are sometimes limited by the
drastic reaction conditions required. Interesting alterna-
OEt
1
a
1b
1c
tive approaches rely, for example, on SmI mediated cou-
2
pling reactions of benzaldehydes with benzylhalides and Scheme 1 Synthesis of 4-(2′-hydroxybenzoyl)salicylic ester 4a
4
b
subsequent oxidation. A number of functionalized sali-
cylic esters have been prepared by cyclization of 1,3-bis-
silyl enol ethers with 1,3-dicarbonyl dielectrophiles and
4
alize a cyclization of 2a with acetoacetate d synthons
4
c–4f
were unsuccessful. The reaction of 2a with the dianion 1b
of ethyl acetetoacetate (1a) resulted in formation of com-
plex mixtures under a variety of conditions. The problem
related methods.
Herein, we wish to report a new and
efficient synthesis of a variety of 4-(2′-hydroxybenz-
oyl)salicylic derivatives by domino ‘Michael–retro-
5
Michael–Wittig’
reactions
of
(2,4-dioxobutyl-
Table 1 Optimization of the Synthesis of 4a
idene)triphenylphosphoranes with 3-formylchromones
6
,7
(
4-oxo-4H-1-benzopyran-3-carboxaldehydes). All re-
Conditions Yield (%)b
Solvent
MeOH
t (h)
48
Base
actions proceed with excellent regioselectivity and use
readily available starting materials.
NaOMe
NaH
Reflux
20 °C
0
23
32
51
58
13
The reaction of 3-formylchromone (2a) with 1,3-dicarbo- THF
nyl compounds resulted in attack of the central carbon
21
THF
3 + 18a
8 + 18a
24
24
NaH
Reflux
Reflux
Reflux
Reflux
atom of the nucleophile onto the aldehyde (aldol conden-
8
sation) and formation of open-chain products. In specific THF
NaH
cases a domino cyclization with ring opening of the
chromone system was observed. Our first attempts to re-
THF
NaH
THF
K CO
2
3
a
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2003,0,02,0402,0404,ftx,en;D21502ST.pdf.
Reflux + 20 °C.
Isolated yield.
b
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
‘Michael–Michael–Wittig’ Reactions of (2,4-Dioxobutylidene)phosphoranes
403
was eventually solved by employment of phosphorane 3a, Table 2 Products and Yields
which is readily available from isopropoxy 4-chloro-
2
a
a
a
a
a
b
c
d
e
f
3
4
a
b
c
d
e
f
R1
R2
H
R3
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
R4
H
%a
58
52
55
54
18
53
55
64
60
53
56
55
acetoacetate. The reaction of 3-formylchromone with
a afforded 4-(2′-hydroxybenzoyl)salicylic ester 4a
Scheme 1). During optimization of the reaction the fol-
3
(
a
O-i-Pr
OEt
b
H
H
lowing parameters proved important (Table 1): a) the
presence of sodium hydride (NaH), b) employment of
THF as the solvent and c) the reaction time (24 h) and
c
OMe
N(CH2)4
NH2
H
H
9
d
H
H
temperature (reflux). Extension of the reaction time to 48
hours did not result in any increase of the yield. The
e
H
H
Me SiOTf catalyzed reaction of 2a with 1,3-bis-silyl enol
3
ether 1c, an electroneutral equivalent of 1b, also resulted
in formation of 4a, however, in low yield.
c
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
Et
H
c
g
h
i
H
The formation of 4a can be explained by a domino
c
i-Pr
Me
Cl
Br
Cl
Br
Cl
NO2
H
‘
Michael–retro-Michael–Wittig’ reaction. Michael reac-
tion of 2a with the central carbon atom of 3a afforded in-
termediate A, which underwent a retro-Michael reaction
to give intermediate B. The latter underwent an intramo-
lecular Wittig reaction to give 4a (Scheme 1). The reac-
tion proceeded with very good regioselectivity which can
be explained as follows: a) In the first step, the Michael re-
action predominated over any aldol or Wittig pathway; b)
the 2′-hydroxybenzoyl moiety of 4a was regiospecifically
formed by cleavage of the chromone system; c) the sali-
cylic moiety was formed by regioselective cyclization.
The structure of 4a was established by spectroscopic
means. The two intramolecular hydrogen bonds O–H⋅⋅⋅O
c
Me
H
c
j
g
h
i
c
k
l
H
c
Cl
Br
H
51b
c
m
n
o
j
c
58
k
c
H
16c
a
b
c
Isolated yield.
Isolated in form of the free acid.
Reaction time: 4 h: 16%, 24 h: 0%
1
could be detected by H NMR.
O
O
H
Ph P
3
R1
O
O
3
a-e
R4
NaH, THF
reflux
Acknowledgment
O
O
R3
R2
P. L. thanks Professor A. de Meijere for his support. Financial
support from the Fonds der Chemischen Industrie e. V. (Liebig-
scholarship for P. L.) and from the Deutsche Forschungsgemein-
schaft (Heisenberg-scholarship for P. L. and Normalverfahren) is
gratefully acknowledged.
O
H
H
R2
+
R3
R1
O
O
R4
4a-o
2
a-k
Scheme 2 Synthesis of 4-(2′-hydroxybenzoyl)salicylic derivatives
a–o
4
References
(
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substituents of the starting materials were systematically
varied (Scheme 2, Table 2). The cyclization of 3-formyl-
chromone (2a) with ethoxy and methoxy substituted
phosphanes 3b and 3c gave the corresponding salicylic es-
ters 4b and 4c, respectively. The cyclization of 2a with
amino-substituted phosphanes 3d,e afforded the salicylic
amides 4d,e. Variation of the chromone moiety was next
studied. The reaction of phosphane 3c with alkyl substi-
tuted formylchromones 2b–e afforded 4-(2′-hydroxyben-
zoyl)salicylic esters 4f–i. Salicylic esters 4j–n were
prepared by reaction of 3c with chloro and bromo substi-
tuted chromones 2f–j. Starting with 2k, nitro substituted
salicylic ester 4o was obtained.
(
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Synlett 2003, No. 3, 402–404 ISSN 0936-5214 © Thieme Stuttgart · New York

4
04
P. Langer, E. Holtz
LETTER
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(
(
5) For reviews of domino reactions, see: (a) Tietze, L. F.;
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(9) Representative Experimental Procedure: A THF
suspension (5 mL) of NaH (78 mg, 3.25 mmol) and 3b (556
mg, 1.43 mmol) was stirred under nitrogen atmosphere at
0 °C for 30 min. A THF solution (10 mL) of 2a (190 mg, 1.1
mmol) was added and the solution was stirred for 60 min at
0 °C. The reaction mixture was refluxed for 24 h, cooled and
subsequently stirred for 12 h at 20 °C. To the mixture was
added diethyl ether (30 mL), an aqueous solution of HCl (5
mL, 1 M) and a saturated solution of NaCl. The aqueous
layer was separated and extracted with CH Cl (3 × 10 mL).
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hydroxybenzoyl)-pyrimidines: Löwe, W. Synthesis 1976,
2
74. (d) See also: Petersen, U.; Heitzer, H. Liebigs Ann.
Chem. 1976, 1663. (e) With enamines: Heber, D. Synthesis
978, 691. (f) With hydrazines: Eiden, F.; Haverland, H.
2
2
1
The combined organic layers were dried (MgSO ), filtered
4
Arch. Pharm. (Weinheim, Ger.) 1968, 301, 819. (g) See
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1
978, 55, 386. (h) With H NOH⋅HCl: Hsung, R. P.;
diethyl ether/petroleum ether = 1:20) to give 4b (52%) as a
2
1
Zificsak, C. A.; Wei, L.-L.; Zehnder, L. R.; Park, F.; Kim,
M.; Tran, T.-T. T. J. Org. Chem. 1999, 64, 8736. (i) With
o-phenylenediamine: Ghosh, C. K.; Khan, S. Synthesis
yellow solid. Spectroscopic data of 4b: H NMR (CDCl ,
3
3
3
250 MHz): δ = 1.42 (t, J = 7 Hz, 3 H, CH ), 4.45 (q, J = 7
Hz, 2 H, OCH CH ), 6.91 (dd, J = 7 Hz, J = 8 Hz, 1 H,
Ar), 7.08 (d, J = 8 Hz, 1 H, Ar), 7.10 (d, J = 8 Hz, 1 H, Ar),
7.53 (dd, J = 7 Hz, J = 8 Hz, 1 H, Ar), 7.59 (d, J = 8 Hz,
3
3
3
2
3
1
2
3
3
1980, 701. (j) For conversions into pyrroles and thiophenes:
3
3
3
Fitton, A. O.; Frost, J. R.; Suschitzky, H.; Hougton, P. G.
Synthesis 1977, 133. (k) For a review on 3-
formylchromones, see: Ellis, G. P. Heterocyclic
1 2
3
1 H, Ar), 7.84 (d, J = 8 Hz, 1 H, Ar), 8.30 (s, 1 H, Ar), 11.34
1
3
(s, 1 H, OH), 11.87 (s, 1 H, OH). C NMR (CDCl , 50
3
Compounds, Vol. 35; Weisberger, A., Ed.; Wiley-
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M.; Ishida, A.; Tanaka, Y.; Ueda, I. Tetrahedron Lett. 1996,
MHz): δ = 14.15 (CH ), 62.07 (CH ), 112.47, 119.03,
3
2
129.00 (C, Ar, ortho and para to OH), 117.74, 118.51,
118.70 (CH, Ar, ortho and para to OH), 132.36, 132.95,
136.18, 136.59 (CH, Ar, meta to OH), 163.00, 164.70,
(
169.61 (C, C–OH, CO Et), 199.12 (C, CO). IR (KBr): 3178
2
(w), 3059 (w), 2987 (w), 2933 (w), 1683 (s), 1629 (s), 1589
(s), 1467 (m), 1444 (m), 1397 (m), 1343 (s), 1293 (s), 1262
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–
1
Lett. 1999, 153.
(s), 1242 (s), 1176 (m), 1084 (m) cm . MS (70 eV): m/z (%)
+
=
286 (100) [M ], 121(94). Anal. Calcd for C H O : C,
16 14 5
67.31; H, 4.93. Found: C, 66.88; H, 5.18. All compounds
gave satisfactory spectroscopic and analytical and/or high
resolution mass data.
Synlett 2003, No. 3, 402–404 ISSN 0936-5214 © Thieme Stuttgart · New York