One-pot reactions of 2,4-(dioxobutylidene)phosphoranes. Efficient synthesis of 4-(2-hydroxybenzoyl)salicylic acid derivatives and buta-1,3-diene-1,4-dicarboxylates

Article abstract of DOI:10.1016/j.tet.2007.02.062

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:10.1016/j.tet.2007.02.062

Tetrahedron 63 (2007) 3293–3301
One-pot reactions of 2,4-(dioxobutylidene)phosphoranes.
Efficient synthesis of 4-(2-hydroxybenzoyl)salicylic acid
derivatives and buta-1,3-diene-1,4-dicarboxylates
Edith Holtz,a Uwe Albrechta and Peter Langera,b,
*
aInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu€r Katalyse e. V. an der Universita€t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 29 January 2007; accepted 15 February 2007
Available online 20 February 2007
Abstract—4-(2-Hydroxybenzoyl)salicylic esters and amides were prepared by domino ‘Michael-Retro-Michael-Wittig’ reactions of
(2,4-dioxobutylidene)triphenylphosphoranes with 3-formylchromones.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the method is limited by the availability of the 1,3-bis(silyl
enol ethers). For example, 4-(2-hydroxybenzoyl)salicylic
amides could not be prepared, since the corresponding
b-ketoamide derived 1,3-bis(silyl enol ethers) are not avail-
able.9 Some years ago, we reported10 an alternative approach
to 4-(2-hydroxybenzoyl)salicylic derivatives based on
domino ‘Michael-Retro-Michael-Wittig’ reactions of 3-for-
mylchromones11 with (2,4-dioxobutylidene)triphenylphos-
phoranes.12,13 Herein, we report full details of these
reactions, which allow inter alia the synthesis of 4-(2-hy-
droxybenzoyl)salicylic amides. In addition, we report, for the
first time, the synthesis of buta-1,3-diene-1,4-dicarboxylates
by the reaction of (2,4-dioxobutylidene)triphenylphosphor-
anes with a-ketoesters.
Functionalized benzophenones occur in a variety of natural
products and represent important core structures for the
development of pharmaceuticals.1 For example, the benzo-
phenone phenstatin and related 2-hydroxy- and 2-aminoben-
zophenones are of considerable relevance in anticancer
therapy as they represent potent antitubulin agents.2,3 We
have recently shown that 4-(2-hydroxybenzoyl)salicylic
esters represent potent E-, P- and L-selectin antagonists
and are, thus, interesting compounds for medical applica-
tions against inflammatory disorders.4 Benzophenones are
widely used as photosensitizers and represent one of the
most important substance classes in photochemistry.5
2-Hydroxybenzophenones are also widely used as UV
filters6 and we have recently reported that 4-(2-hydroxy-
benzoyl)salicylic esters represent promising candidates for
the development of novel UV filters.4
2. Results and discussion
The reaction of 3-formylchromone with phosphorane 2a
afforded 4-(2-hydroxybenzoyl)salicylic ester 3a (Scheme
1). During optimization of the reaction the following para-
meters 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 temperature (reflux). Exten-
sion of the reaction time to 48 h did not result in any increase
of the yield. The formation of 3a can be explained by a
domino ‘Michael-Retro-Michael-Wittig’ reaction. Michael
reaction of 1a with the central carbon atom of 2a afforded
intermediate A, which underwent a Retro-Michael reaction
to give intermediate B. The latter underwent an intramolec-
ular Wittig reaction to give 3a (Scheme 1). The reaction
proceeded with very good regioselectivity, which can be ex-
plained as follows: (a) In the first step, the Michael reaction
predominated over any aldol or Wittig pathway; (b) the
2-hydroxybenzoyl moiety of 3a was regiospecifically
Classic syntheses of benzophenones rely on reactions of
aryllithium or magnesium reagents with aldehydes and
subsequent oxidation3a,7 and on Friedel–Crafts acylations.8
The application of these methods to the synthesis of func-
tionalized benzophenones (e.g., containing a hydroxy, halide
or ester group) can result in competing side reactions.
Recently, we reported4 the synthesis of 4-(2-hydroxy-
benzoyl)salicylates by domino ‘Michael-retro-Michael-
Mukaiyama-aldol’ reactions of 3-formylchromones with
1,3-bis(silyl enol ethers). The preparative scope of this
method is relatively broad and most of the products were
isolated in moderate to good yields (42–63%). Notably,
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412;
e-mail: peter.langer@uni-rostock.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.062

3294
E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
O
O
Variation of the chromone moiety was next studied. The re-
H
Ph3P
action of phosphane 2c with alkyl substituted formylchro-
mones 1b–e afforded 4-(20-hydroxybenzoyl)salicylic esters
3g–j. Salicylic esters 3k–o were prepared by the reaction
of 2c with chloro and bromo substituted chromones 1f–j.
Starting with 1k, nitro substituted salicylic ester 3p was ob-
tained, albeit, in low yield.
O
O
OiPr
2a
O
O
O
i
O
H
H
+
iPrO
3a (58%)
O
1a
The structures of 3a–p were established by spectroscopic
methods. The two intramolecular hydrogen bonds O–H/O
could be detected by H NMR. The structures of 3e and 3o
were independently confirmed by X-ray crystal structure
analyses (Figs. 1 and 2).14
- Ph3P=O
1
O
O
O
O
O
H
O
PPh3
H
O
PPh3
O
O
OH
iPrO
Buta-1,3-diene-1,4-dicarboxylates represent potentially use-
ful synthetic building blocks, which have only scarcely been
reported in the literature to date. Known syntheses rely on
the hydrolysis of g-alkylidenebutenolides,15 on the reaction
of malonates with fumaric acid derivatives, and on addition
reactions to diynoates.16 Ketipinates (2,3-di(hydroxyl)hexa-
1,3-diene-1,4-dicarboxylates) are available by the reaction
of dimethyl malonate with oxalyl chloride and related reac-
tions.17 Herein, we report a new and efficient approach to
2-(hydroxy)buta-1,3-diene-1,4-dicarboxylates by the reac-
tion of (2,4-dioxobutylidene)phosphoranes with a-ketoesters.
iPrO
B
A
Scheme 1. Synthesis of 4-(2-hydroxybenzoyl)salicylate 3a. Reagents: (i)
NaH, THF, reflux.
Table 1. Products and yields
a
%
1
2
3
R1
R2
R3
R4
a
a
a
a
a
a
b
c
d
e
f
g
h
i
j
k
a
b
c
d
e
f
c
c
c
c
c
c
c
c
c
c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
O-i-Pr
OEt
OMe
NH2
H
H
H
H
H
H
Me
Et
i-Pr
Me
Cl
Br
Cl
Br
Cl
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
H
H
Cl
Br
H
H
58
52
55
18
54
25
53
55
64
60
53
56
55
51b
58
16c
The reaction of ethyl 2-oxopropionate (4) with phosphoranes
2c, 2b, 2e and 2g afforded the buta-1,3-diene-1,4-dicarboxy-
lates 5a–d in moderate to good yields, respectively
N(CH2)4
N(CH2)5
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
a
b
c
Isolated yields.
Isolated in form of the free acid.
Reaction time—4 h: 16%, 24 h: 0%.
formed by cleavage of the chromone system; (c) the salicylic
moiety was formed by regioselective cyclization.
Figure 1. ORTEP plot of 3e.
To study the preparative scope of our methodology, the sub-
stituents of the starting materials were systematically varied
(Scheme 2, Table 1). The cyclization of 3-formylchromone
(1a) with ethoxy and methoxy substituted phosphanes 2b
and 2c gave the corresponding salicylic esters 3b and 3c,
respectively. The cyclization of 1a with amino-substituted
phosphanes 2d–f afforded the salicylic amides 3d–f.
O
O
Ph3P
R1
OH
O
2a-f
R4
R3
+
O
O
i
R2
OH
H
R2
R1
O
R3
O
R4
3a-p
1a-k
Scheme 2. Synthesis of 4-(2-hydroxybenzoyl)salicylic acid derivatives
3a–p. Reagents: (i) NaH, THF, reflux.
Figure 2. ORTEP plot of 3o.

E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
3295
(Scheme 3, Table 2). All products were isolated as a single
E/Z-diastereomer. They exclusively exist in their enol tauto-
meric form.
3. Experimental section
3.1. General
Me
3.1.1. Methyl 4-(triphenylphosphoranylidene)acetoace-
tate (2c). The synthesis of 2c has been previously reported.19
To the best of our knowledge, NMR spectroscopic data have
not yet been reported. A benzene solution (50 mL) of triphe-
nylphosphane (20.30 g, 77.0 mmol) and of methyl 4-chloro-
acetoacetate (12.80 g, 85.0 mmol) was stirred at 50 ꢀC for
24 h. After cooling, the precipitate formed was filtered off,
washed with benzene and dissolved in water. A saturated
aqueous solution of sodium bicarbonate was added and the
precipitate formed was filtered off, washed with water and
dried in vacuo to give 2c (20.80 g, 72%) as a colourless solid.
1H NMR (250 MHz, CDCl3): d¼3.37 (s, 2H, CH2), 3.73 (s,
3H, CH3), 3.80–3.95 (br s, 1H, P]CH), 7.40–7.70 (m, 15H,
EtO
O
Me OH
O
O
i
4
EtO
R
O
O
O
+
Ph3P
R
2b,c,e,g
5a-d
Scheme 3. Synthesis of hexa-2,4-diene-1,6-dicarboxylates 5a–d. Condi-
tions: (i) 80 ꢀC, 2 h.
Table 2. Products and yields
2
5
R
%a (A)
%a (B)
Keto/enolc
c
b
e
g
a
b
c
OMe
OEt
NC4H8
Ph
76
80
—
—
50
50
48
49
1:2
1:1
CH, Ph). 13C NMR (50.3 MHz, CDCl3): d¼48.0 (d, 3JC–P
¼
b
1
1:2
>2:98
16 Hz, CH2, O]C–CH2), 51.8 (CH3), 52.5 (d, JC–P
108 Hz, P]CH), 126.5 (d, JC–P¼91 Hz, C, Ph), 128.8 (d,
¼
b
1
d
2JC–P¼13 Hz, CH, Ph, ortho), 132.1 (d, JC–P¼3 Hz, CH,
4
a
Isolated yields; method A: neat, 80 ꢀC; method B: toluene or benzene,
reflux, 5 h.
Experiment not carried out.
3
Ph, para), 133.1 (d, JC–P¼10 Hz, CH, Ph, meta), 171.1
b
c
2
(CO, ester), 183.7 (d, JC–P¼3 Hz, CO, ketone). MS (EI,
By 1H NMR (CDCl3).
70 eV): 376 [M+] (13), 304 (20), 303 (100).
The condensation of phosphoranes 2 with ethyl glyoxylate
was next studied. Ethyl glyoxylate is available by oxidative
cleavage of diethyl tartrate. However, in our hands, 6 could
not be prepared with sufficient purity. Recently, a one-pot
synthesis of alkenes by in situ oxidation of primary alcohols
and subsequent Wittig reaction has been reported.18 We
studied the application of this procedure to the reaction of
ethyl 2-hydroxyacetate (6) with phosphorane 2c. Initial re-
sults showed that the reaction of 2c with ethyl glyoxylate
(7), in situ generated by Swern oxidation of 6, resulted in
the formation of the desired diene 8a. Optimal results were
obtained when MnO2 (10 equiv) was used as an oxidizing
agent (CH2Cl2, 20 ꢀC, 24 h). Following this procedure,
hexa-2,4-dienes 8a and 8b were prepared in 52 and 51%
yield, respectively (Scheme 4, Table 3). Again, all products
were isolated as a single E/Z-diastereomer and exclusively
exist in their enol tautomeric form.
3.1.2. 4-(Triphenylphosphoranylidene)acetoacetic acid
amide (2d). The synthesis of 2d has been previously re-
ported.20 To the best of our knowledge, spectroscopic data
have not yet been reported. Compound 2b (3.90 g,
10.0 mmol) was stirred for 10 days in a MeOH solution
(10 mL) saturated with ammonia. The precipitated product
was recrystallized from benzene to give 2d (2.70 g, 74%) as
1
a colourless solid. H NMR (250 MHz, CDCl3): d¼3.30 (s,
2
2H, O]C–CH2), 3.87 (d, JH–P¼26 Hz, 1H, P]CH), 5.84
(br s, 1H, NH2), 7.30–7.70 (m, 15H, CH, Ph), 8.19 (br, 1H,
¼
3
NH2). 13C NMR (50.3 MHz, CDCl3): d¼47.2 (d, JC–P
1
16 Hz, CH2, O]C–CH2), 55.3 (d, JC–P¼107 Hz, P]CH),
125.9 (d, 1JC–P¼91 Hz, C, Ph), 129.0 (d, 2JC–P¼12 Hz, CH,
4
Ph, ortho), 132.4 (d, JC–P¼3 Hz, CH, Ph, para), 132.9 (d,
3JC–P¼10 Hz, CH, Ph, meta), 172.2 (CO, amide), 186.1 (d,
2JC–P¼3 Hz, CO, ketone). MS (EI, 70 eV): 361 [M+] (14),
303 (100). Anal. Calcd for C22H20O2NP: C, 73.12; H, 5.58;
N, 3.88. Found: C, 72.55; H, 5.38; N, 3.53.
O
O
Ph3P
OR
O
3.1.3. 4-(Triphenylphosphoranylidene)acetoacetic acid
pyrrolidide (2e). The synthesis of 2e has been previously
reported.21 To the best of our knowledge, spectroscopic
data have not yet been reported. A toluene solution
(25 mL) of 2b (5.80 g, 19.0 mmol), pyrrolidine (2.70 g,
38.0 mmol) and DMAP (0.69 g, 6.0 mmol, 30 mol %) was
stirred under reflux for 10 h. The solution was concentrated
and cooled to 0 ꢀC to give a precipitate. The latter was
recrystallized from EtOH to give 2e (6.20 g, 79%) as a
colourless solid. 1H NMR (250 MHz, CDCl3): d¼1.80–
1.90 (m, 4H, CH2), 3.36 (s, 2H, O]C–CH2), 3.48 (t,
3J¼7 Hz, 3H, N–CH2), 3.56 (t, 3J¼6 Hz, 3H, N–CH2),
2b,c
RO
i
OEt
O
O
OH
8a,b
+
OH
EtO
6
O
O
EtO
7
Scheme 4. Synthesis of hexa-2,4-dienes 8a,b. Reagents and conditions:
MnO2 (10 equiv), CH2Cl2, 20 ꢀC, 24 h.
2
3.91 (d, JH–P¼24 Hz, 1H, P]CH), 7.35–7.70 (m, 15H,
Table 3. Synthesis of hexa-2,4-dienes 8a,b
CH, Ph). 13C NMR (50.3 MHz, CDCl3): d¼24.5, 26.0
a
2
8
R
%
keto/enolb
3
(CH2), 45.7, 47.3 (N–CH2), 50.0 (d, JC–P¼15 Hz,
1
c
b
a
b
OMe
OEt
52
51
>2:98
>2:98
CH2, O]C–CH2), 51.9 (d, JC–P¼108 Hz, P]CH), 126.6
1
2
(d, JC–P¼91 Hz, C, Ph), 128.7 (d, JC–P¼12 Hz, CH, Ph,
4
a
ortho), 132.0 (d, JC–P¼3 Hz, CH, Ph, para), 133.0 (d,
Isolated yields.
By 1H NMR (CDCl3).
3JC–P¼10 Hz, CH, Ph, meta), 168.9 (CO, amide), 185.4 (d,
b

3296
E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
2JC–P¼3 Hz, CO, ketone). MS (70 eV, EI): 415 [M+] (11),
303 (100), 262 (51). Anal. Calcd for C22H26O2NP: C,
75.63; H, 6.53; N, 3.26. Found: C, 75.93; H, 6.95; N, 3.04.
(m), 2936 (m), 1672 (s), 1629 (s), 1588 (s), 1485 (s), 1338
(s), 1296 (s), 1217 (s), 1106 (m), 799 (m), 759 (s), 632
(m). MS (70 eV, EI): m/z (%)¼300 [M+] (80), 121 (100),
120 (94). Anal. Calcd for C17H16O5 (300.31): C, 67.99; H,
5.37. Found: C, 68.13; H, 5.18.
3.1.4. 4-(Triphenylphosphoranylidene)acetoacetic acid
piperidide (2f). A toluene solution (25 mL) of 2b (5.90 g,
19.0 mmol), piperidine (3.20 g, 38.0 mmol) and DMAP
(0.69 g, 6.0 mmol, 30 mol %) was stirred under reflux for
10 h. The solution was concentrated and cooled to 0 ꢀC to
give a precipitate. The latter was recrystallized from EtOH
3.2.2. 2-Hydroxy-5-(2-hydroxybenzoyl)benzoic acid
ethyl ester (3b). Phosphorane 2b (556.4 mg, 1.43 mmol,
1.3 equiv), formylchromone 1a (189.5 mg, 1.09 mmol) and
NaH (77.9 mg, 3.25 mmol, 3.0 equiv) were reacted accord-
ing to the general procedure (reflux time 5 h). After column
chromatography (silica gel, petroleum ether/ether¼20:1),
3b could be isolated as a yellow solid (130 mg, 42%);
Rf¼0.36. 1H NMR (250 MHz, CDCl3): d¼1.42 (t, 3J¼
1
to give 2f (6.40 g, 79%) as a colourless solid. H NMR
(250 MHz, CDCl3): d¼1.40–1.60 (m, 6H, CH2), 3.42 (s,
2H, O]C–CH2), 3.50–3.60 (m, 4H, N–CH2), 3.88 (d,
2JH–P¼24 Hz, 1H, P]CH), 7.35–7.70 (m, 15H, CH, Ph).
13C NMR (50.3 MHz, CDCl3): d¼24.5, 25.6, 26.1 (CH2),
3
7 Hz, 3H, CH3), 4.45 (q, J¼7 Hz, 2H, CH2), 6.91 (dd,
3
3
42.7, 47.5 (N–CH2), 49.5 (d, JC–P¼15 Hz, CH2, O]
3J¼7, 8 Hz, 1H, Ar), 7.08 (d, J¼8 Hz, 1H, Ar), 7.09 (d,
C–CH2), 51.5 (d, 1JC–P¼109 Hz, P]CH), 126.6 (d, 1JC–P
¼
3J¼8 Hz, 1H, Ar), 7.53 (dd, J¼7, 8 Hz, 1H, Ar), 7.59 (d,
3
91 Hz, C, Ph), 128.7 (d, 2JC–P¼12 Hz, CH, Ph, ortho), 132.0
3J¼8 Hz, 1H, Ar), 7.84 (d, J¼8 Hz, 1H, Ar), 8.30 (s, 1H,
3
4
3
(d, JC–P¼3 Hz, CH, Ph, para), 132.98, 133.99 (d, JC–P
¼
¼
Ar), 11.34 (s, 1H, OH), 11.87 (s, 1H, OH). 13C NMR
(50.3 MHz, CDCl3): d¼14.1 (CH3), 62.1 (CH2), 112.5 (C,
Ar), 117.7, 118.5, 118.7 (CH, Ar), 119.0, 129.0 (C, Ar),
132.4, 132.9, 136.2, 136.6 (CH, Ar), 163.0, 164.7, 169.6
(COH, COOR), 199.1 (CO). IR (KBr, cmꢁ1): ~n¼
3187 ðwÞ, 3087 (w), 2987 (w), 2966 (w), 1683 (s), 1629
(s), 1589 (s), 1467 (m), 1444 (m), 1397 (m), 1343 (s),
1293 (s), 1242 (s), 1216 (s), 1176 (m), 1084 (m), 759 (s).
MS (70 eV, EI): m/z (%)¼286 [M+] (100), 121 (94), 120
(86). Anal. Calcd for C16H14O5 (286.28): C, 67.31; H,
4.93. Found: C, 66.88; H, 5.18.
10 Hz, CH, Ph, meta), 168.9 (CO, amide), 185.3 (d, 2JC–P
3 Hz, CO, ketone). IR (KBr, cmꢁ1): ~n¼2945 ðmÞ, 2856 (w),
16.28 (s), 1548 (s), 1440 (s), 1384 (s), 1271 (m), 1106 (s),
861 (m), 760 (m), 718 (m), 696 (m), 540 (m), 527 (m).
MS (70 eV, EI): 429 [M+] (12), 318 (27), 303 (100), 262
(40). HRMS (EI, 70 eV): calcd for C23H28O2NP (M+):
429.1858; found: 429.1858ꢂ3 ppm.
3.2. General procedure for the synthesis of the
4-(20-hydroxybenzoyl)salicylic acid derivatives 3a–p
A THF suspension (5 mL) of NaH (2.6–5.1 equiv) and of
phosphorane 2 (1.3–1.4 equiv) was stirred under nitrogen
atmosphere at 0 ꢀC for 30 min. Then a THF solution
(10 mL) of the formylchromone 1 (1.0 equiv) was added
and the resulting solution was stirred for further 60 min at
0 ꢀC. Thereafter the reaction mixture was refluxed for the
specified time, cooled to room temperature and stirred for
12 h at 20 ꢀC. To the mixture was added an aqueous solution
of hydrochloric acid (5 mL, 1 M), a saturated solution of
NaCl (10 mL) and ether (30 mL). The aqueous layer was
separated and extracted with CH2Cl2 (3ꢃ10 mL). The com-
bined organic layers were dried (MgSO4), filtered and the
solvent of the filtrate was removed in vacuo. Purification
of the residue was performed by column chromatography.
3.2.3. 2-Hydroxy-5-(2-hydroxybenzoyl)benzoic acid
methyl ester (3c). Phosphorane 2c (519.5 mg, 1.38 mmol,
1.3 equiv), formylchromone 1a (184.8 mg, 1.06 mmol) and
NaH (127.6 mg, 5.31 mmol, 5.0 equiv) were reacted accord-
ing to the general procedure (reflux time 14 h). After column
chromatography (silica gel, petroleum ether/ether¼10:1), 3c
could be isolated as a yellow solid (155 mg, 54%); Rf¼0.51.
1H NMR (250 MHz, CDCl3): d¼3.98 (s, 3H, CH3), 6.90 (dd,
3J¼7, 8 Hz, 1H, Ar), 7.08 (d, 3J¼8 Hz, 1H, Ar), 7.10 (d, 3J¼
9 Hz, 1H, Ar), 7.45–7.60 (m, 2H, Ar), 7.86 (d, 3J¼9 Hz, 1H,
Ar), 8.28 (s, 1H, Ar), 11.23 (s, 1H, OH), 11.84 (s, 1H, OH).
13C NMR (75.5 MHz, CDCl3): d¼52.7 (CH3), 112.1 (C, Ar),
117.8, 118.5, 118.7 (CH, Ar), 119.0, 129.0 (C, Ar), 132.4,
132.9, 136.1, 136.7 (CH, Ar), 162.9, 164.6, 169.9 (COH,
COOR), 198.96 (CO). IR (KBr, cmꢁ1): ~n¼3079 ðwÞ,
3045 (w), 2957 (w), 2923 (w), 1687 (s), 1628 (s), 1588 (s),
1445 (s), 1352 (s), 1292 (s), 1241 (s), 1221 (s), 1168
(m), 1088 (m), 757 (s). MS (70 eV, EI): m/z (%)¼272
[M+] (100), 147 (31), 121 (95), 120 (94). HRMS (EI,
70 eV): calcd for C15H12O5 (M+): 272.0685; found:
272.0685ꢂ3 ppm. Anal. Calcd for C15H12O5 (272.26): C,
66.17; H, 4.44. Found: C, 66.35; H, 4.38.
3.2.1. 2-Hydroxy-5-(2-hydroxybenzoyl)benzoic acid iso-
propyl ester (3a). Phosphorane 2a (638.4 mg, 1.58 mmol,
1.3 equiv), formylchromone 1a (210.8 mg, 1.21 mmol) and
NaH (111.5 mg, 4.65 mmol, 3.8 equiv) were reacted accord-
ing to the general procedure (reflux time 27 h). After column
chromatography (silica gel, petroleum ether/ether¼20:1),
3a could be isolated as a yellow solid (209.5 mg, 58%);
Rf¼0.50. 1H NMR (250 MHz, CDCl3): d¼1.40 (d,
3J¼6 Hz, 6H, 2ꢃCH3), 5.32 (sept, 3J¼6 Hz, 1H,
OCH(CH3)2), 6.90 (dd, 3J¼7, 8 Hz, 1H, Ar), 7.07 (d,
3.2.4. 2-Hydroxy-5-(2-hydroxybenzoyl)benzamide (3d).
Phosphorane 2d (536.5 mg, 148 mmol, 1.3 equiv), formyl-
chromone 1a (199.3 mg, 1.14 mmol) and NaH (85.9 mg,
3.58 mmol, 3.1 equiv) were reacted according to the general
procedure (reflux time 25 h). After column chromatography
(silica gel, petroleum ether/ether¼1:1), 3d could be isolated
3
3J¼7 Hz, 1H, Ar), 7.08 (d, J¼8 Hz, 1H, Ar), 7.47–7.60
3
4
(m, 2H, Ar), 7.82 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar), 8.29
4
(d, J¼2 Hz, 1H, Ar), 11.44 (s, 1H, OH), 11.88 (s, 1H,
OH). 13C NMR (75.5 MHz, CDCl3): d¼21.77 (2ꢃCH3),
70.12 (OCH(CH3)2), 112.9 (C, Ar), 117.6, 118.5, 118.6
(CH, Ar), 119.0, 128.9 (C, Ar), 132.3, 132.9, 136.2, 136.5
(CH, Ar), 163.0, 164.7, 169.2 (COH, COOR), 199.2 (CO).
IR (KBr, cmꢁ1): ~n¼3396 ðwÞ, 3350 (w), 3069 (m), 2984
1
as a pale yellow solid (49.0 mg, 17%); Rf¼0.31. H NMR
(200 MHz, acetone-d6): d¼2.83 (br s, 2H, NH2), 6.90–
3
7.10 (m, 2H, Ar), 7.07 (d, J¼9 Hz, 1H, Ar), 7.57 (dd,
3
3
3J¼9 Hz, J¼8 Hz, 1H, Ar), 7.66 (d, J¼9 Hz, 1H, Ar),

E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
3297
7.85 (dd, 3J¼8 Hz, 4J¼2 Hz, 1H, Ar), 8.28 (d, 4J¼2 Hz, 1H,
Ar), 11.10–11.30 (br s, 1H, OH), 11.62 (s, 1H, OH). 13C
NMR (50.3 MHz, pyridine-d5): d¼115.6 (C, Ar), 118.1,
118.3, 119.3 (CH, Ar), 129.1 (C, Ar), 131.39, 132.41,
134.8 (CH, Ar), 135.8 (C, Ar), 136.2 (CH, Ar), 160.8,
166.3, 173.0 (COH, COOR), 197.9 (CO). IR (KBr, cmꢁ1):
~n¼3400 ðsÞ, 3191 (s), 2925 (m), 1699 (s), 1637 (s), 1626
(s), 1597 (s), 1490 (s), 1337 (s), 1245 (s), 1158 (m), 979
(m), 833 (m), 761 (s). MS (70 eV, EI): m/z (%)¼257 [M+]
(100), 121 (70), 120 (83). HRMS (EI, 70 eV): calcd for
C14H11NO4 (M+): 257.0688; found: 257.0688ꢂ3 ppm.
1.39 mmol, 1.4 equiv), formylchromone 1b (189.9 mg,
1.01 mmol) and NaH (82.3 mg, 3.42 mmol, 3.4 equiv)
were reacted according to the general procedure (reflux
time 8 h). After column chromatography (silica gel, petro-
leum ether/ether¼20:1), 3g could be isolated as a yellow
solid (154.6 mg, 53%); Rf¼0.22. 1H NMR (250 MHz,
CDCl3): d¼2.28 (s, 3H, CH3), 3.98 (s, 3H, OCH3), 6.99
3
3
(d, J¼9 Hz, 1H, Ar), 7.10 (d, J¼9 Hz, 1H, Ar), 7.30–
3
4
7.40 (m, 2H, Ar), 7.84 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar),
4
8.27 (d, J¼2 Hz, 1H, Ar), 11.22 (s, 1H, OH), 11.64 (s,
1H, OH). 13C NMR (50.3 MHz, CDCl3): d¼23.9 (CH3),
52.72 (OCH3), 112.2 (C, Ar), 117.7, 118.3 (CH, Ar),
118.7, 127.9, 129.2 (C, Ar), 132.3, 132.6, 136.6, 137.2
(CH, Ar), 160.9, 164.5, 170.0 (COH, COOR), 199.0 (CO).
IR (KBr, cmꢁ1): ~n¼3064 ðmÞ, 2961 (m), 2925 (w),
1677 (s), 1584 (s), 1481 (s), 1358 (s), 1295 (s), 1220 (s),
1204 (s), 1088 (m), 955 (w), 794 (s), 640 (m). MS (70 eV,
EI): m/z (%)¼286 [M+] (54), 135 (48), 134 (100). Anal.
Calcd for C16H14O5 (286.28): C, 67.31; H, 4.93. Found: C,
66.99; H, 5.00.
3.2.5. [2-Hydroxy-5-(2-hydroxybenzoyl)phenyl]pyr-
rolidin-1-yl-methanone (3e). Phosphorane 2e (438.1 mg,
1.06 mmol, 1.3 equiv), formylchromone 1a (438.1 mg,
1.06 mmol, 1.3 equiv) and NaH (77.4 mg, 3.23 mmol,
3.9 equiv) were reacted according to the general procedure
(reflux time 25 h). After column chromatography (silica
gel, petroleum ether/ether¼1:1), 3e could be isolated as
1
a pale yellow solid (113.9 mg, 44%); Rf¼0.23. H NMR
(250 MHz, CDCl3) d¼1.90–2.05 (m, 4H, 2ꢃCH2), 3.60–
3
3.90 (m, 4H, 2ꢃNCH2), 6.90 (dd, J¼8, 7 Hz, 1H, Ar),
3.2.8. 5-(5-Ethyl-2-hydroxybenzoyl)-2-hydroxybenzoic
acid methyl ester (3h). Phosphorane 2c (458.7 mg,
1.22 mmol, 1.4 equiv), formylchromone 1c (180.5 mg,
0.89 mmol) and NaH (71.3 mg, 2.97 mmol, 3.3 equiv)
were reacted according to the general procedure (reflux
time 14 h). After column chromatography (silica gel, petro-
leum ether/ether¼10:1), 3h could be isolated as yellow solid
(146 mg, 55%); Rf¼0.30. 1H NMR (250 MHz, CDCl3):
d¼1.19 (t, 3J¼8 Hz, 3H, CH3), 2.57 (q, 3J¼8 Hz, 2H,
CH2), 3.98 (s, 3H, OCH3), 7.01 (d, 3J¼9 Hz, 1H, Ar), 7.11
3
3
7.07 (d, J¼9 Hz, 2H, CH, Ar), 7.51 (dd, J¼8, 7 Hz, 1H,
Ar), 7.59 (d, 3J¼8 Hz, 1H, Ar), 7.75 (dd, 3J¼9 Hz,
4J¼2 Hz, 1H, Ar), 7.96 (d, J¼2 Hz, 1H, Ar), 11.81 (s,
4
1H, OH), 12.10 (s, 1H, OH). 13C NMR (50.3 MHz,
CDCl3) d¼24.1, 26.9 (2ꢃCH2), 47.9, 50.5 (2ꢃNCH2),
116.8 (C, Ar), 117.7, 118.5, 118.6 (CH, Ar), 119.1, 127.7
(C, Ar), 130.7, 132.8, 134.5, 136.0 (CH, Ar), 162.8, 164.3,
169.2 (COH, COOR), 199.1 (CO). IR (KBr, cmꢁ1):
~n¼3427 ðmÞ, 3128 (s), 2974 (m), 2885 (m), 1618 (s),
1588 (s), 1483 (s), 1455 (s), 1293 (s), 1256 (s), 1170 (m),
846 (m), 762 (s), 626 (m). MS (70 eV, EI): m/z (%)¼311
[M+] (100), 241 (29), 70 (50). Anal. Calcd for C18H17NO4
(311.34): C, 69.44; H, 5.50. Found: C, 69.21; H, 5.75.
3
(d, J¼9 Hz, 1H, Ar), 7.30–7.40 (m, 2H, Ar), 7.87 (dd,
4
4
3J¼9 Hz, J¼2 Hz, 1H, Ar), 8.29 (d, J¼2 Hz, 1H, Ar),
11.22 (s, 1H, OH), 11.64 (s, 1H, OH). 13C NMR
(75.5 MHz, CDCl3): d¼15.8 (CH3), 27.9 (CH2), 52.7
(OCH3), 112.1 (C, Ar), 117.8, 118.3 (CH, Ar), 118.7,
129.2 (C, Ar), 131.5, 132.6 (CH, Ar), 134.3 (C, Ar), 136.1,
136.7 (CH, Ar), 161.0, 164.5, 170.0 (COH, COOR), 198.9
(C, CO). IR (KBr, cmꢁ1): ~n¼3407 ðwÞ, 3098 (m), 3070
(m), 2965 (m), 1676 (s), 1585 (s), 1356 (s), 1291 (s), 1216
(s), 1200 (s), 1085 (m), 984 (m), 795 (s), 639 (m). MS
(70 eV, EI): m/z (%)¼300 [M+] (59), 149 (36), 148 (100),
133 (31). HRMS (EI, 70 eV): calcd for C17H16O5 (M+):
300.0998; found: 300.0998ꢂ3 ppm.
3.2.6. [2-Hydroxy-5-(2-hydroxybenzoyl)phenyl]piperi-
din-1-yl-methanone (3f). Phosphorane 2f (567 mg,
1.33 mmol, 1.3 equiv), formylchromone 1a (173 mg,
0.99 mmol) and NaH (78.6 mg, 3.25 mmol, 3.3 equiv)
were reacted according to the general procedure (reflux
time 25 h). After column chromatography (silica gel, petro-
leum ether/ether¼2:1), 3f could be isolated as a pale yellow
solid (79.3 mg, 25%); Rf¼0.24. 1H NMR (250 MHz,
CDCl3): d¼1.55–1.80 (m, 6H, 3ꢃCH2), 3.60–3.75 (m, 4H,
3
3
2ꢃNCH2), 6.90 (dd, J¼8, 7 Hz, 1H, Ar), 7.08 (d, J¼
3.2.9. 2-Hydroxy-5-(2-hydroxy-5-isopropylbenzoyl)benz-
oic acid methyl ester (3i). Phosphorane 2c (512.1 mg,
1.36 mmol, 1.4 equiv), formylchromone 1d (211.6 mg,
0.98 mmol) and NaH (120.3 mg, 5.01 mmol, 5.1 equiv)
were reacted according to the general procedure (reflux
time 4 h). After column chromatography (silica gel, petro-
leum ether/ether¼20:1), 3i could be isolated as a yellow
oil (197.1 mg, 64%); Rf¼0.35. 1H NMR (250 MHz,
CDCl3): d¼1.20 (d, 3J¼7 Hz, 6H, 2ꢃCH3), 2.85 (sept,
3J¼7 Hz, 1H, CH(Me)2), 3.97 (s, 3H, OCH3), 7.01 (d,
3
3
8 Hz, 1H, Ar), 7.11 (d, J¼8 Hz, 1H, Ar), 7.52 (dd, J¼9,
3
4
7 Hz, 1H, Ar), 7.59 (dd, J¼8 Hz, 1H, J¼2 Hz, 1H, Ar),
4
3
4
7.69 (d, J¼2 Hz, 1H, Ar), 7.75 (dd, J¼9 Hz, J¼2 Hz,
1H, Ar), 10.47 (s, 1H, OH), 11.83 (s, 1H, OH). 13C NMR
(125.7 MHz, CDCl3): d¼14.4, 26.1 (CH2), 47.1 (CH2,
NCH2), 116.9 (C, Ar), 118.0, 118.6, 118.6 (CH, Ar),
119.2, 128.3 (C, Ar), 130.6, 132.8, 134.1, 136.1 (CH, Ar),
163.0, 163.1, 169.8 (COH, COOR), 199.1 (CO). IR (KBr,
cmꢁ1): ~n¼3431 ðmÞ, 3020 (m), 2935 (s), 2859 (s), 1629
(s), 1562 (s), 1480 (s), 1449 (s), 1289 (s), 1242 (s), 1137
(s), 967 (m), 765 (m), 655 (m). MS (EI, 70 eV): m/z
(%)¼325 (87), 324 (33), 121 (37), 84 (100). HRMS (EI,
70 eV): calcd for C19H19NO4 (M+): 325.1314; found:
325.1314ꢂ3 ppm.
3
3J¼9 Hz, 1H, Ar), 7.11 (d, J¼9 Hz, 1H, Ar), 7.35–7.45
3
4
(m, 2H, Ar), 7.89 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar), 8.31
4
(d, J¼2 Hz, 1H, Ar), 11.21 (s, 1H, OH), 11.62 (s, 1H,
OH). 13C NMR (75.5 MHz, CDCl3): d¼23.9 (CH3), 33.2
(CH), 52.7 (OCH3), 112.0 (C, Ar), 117.9, 118.2 (CH, Ar),
118.2, 129.1 (C, Ar), 130.2, 132.8, 134.7, 136.7 (CH, Ar),
139.0 (C, Ar), 161.0, 164.6, 167.0 (COH, COOR), 198.8
(CO). IR (KBr, cmꢁ1): ~n¼3144 ðwÞ, 2959 (m), 1681 (s),
3.2.7. 2-Hydroxy-5-(2-hydroxy-5-methylbenzoyl)benzoic
acid methyl ester (3g). Phosphorane 2c (523.8 mg,

3298
E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
1631 (s), 1484 (s), 1443 (m), 1354 (s), 1296 (s), 1213 (s),
1088 (m), 959 (w), 794 (m), 638 (m). MS (70 eV, EI): m/z
(%)¼314 [M+] (89), 299 (27), 163 (21), 162 (50), 147
(100). HRMS (EI, 70 eV): calcd for C18H18O5 (M+):
314.1154; found: 314.1154ꢂ3 ppm.
11.29 (s, 1H, OH), 11.72 (s, 1H, OH). 13C NMR
(75.5 MHz, CDCl3): d¼52.8 (OCH3), 110.3, 112.4 (C, Ar),
118.1 (CH, Ar), 120.3 (C, Ar), 120.5 (CH, Ar), 128.4 (C,
Ar), 132.4, 134.8, 136.5, 138.7 (CH, Ar), 161.8, 164.9,
169.8 (COH, COOR), 197.7 (CO). IR (KBr, cmꢁ1):
~n¼3429 ðwÞ, 3111 (w), 2959 (w), 1686 (s), 1625 (s),
1585 (m), 1469 (m), 1357 (s), 1288 (m), 1216 (s), 1088
(w), 801 (m), 636 (w). MS (70 eV, EI): m/z (%)¼352
([M+], 81Br) (100), 350 ([M+], 79Br) (100), 200 (71), 198
(69), 147 (48), 120 (66). Anal. Calcd for C15H11O5Br
(351.15): C, 51.31; H, 3.16. Found: C, 51.17, H, 3.30.
3.2.10. 2-Hydroxy-5-(2-hydroxy-3,5-dimethylbenzoyl)-
benzoic acid methyl ester (3j). Phosphorane 2c
(467.3 mg, 1.24 mmol, 1.3 equiv), formylchromone 1e
(188.6 mg, 0.93 mmol) and NaH (57.2 mg, 2.38 mmol,
2.6 equiv) were reacted according to the general procedure
(reflux time 5 h). After column chromatography (silica gel,
petroleum ether/ether¼20:1), 3j could be isolated as a yellow
solid (168.7 mg, 60%); Rf¼0.49. 1H NMR (250 MHz,
CDCl3): d¼2.24 (s, 3H, CH3), 2.29 (s, 3H, CH3), 3.98 (s,
3.2.13. 5-(3,5-Dichloro-2-hydroxybenzoyl)-2-hydroxy-
benzoic acid methyl ester (3m). Phosphorane 2c
(570.9 mg, 1.52 mmol, 1.3 equiv), formylchromone 1h
(275.2 mg, 1.13 mmol) and NaH (68.2 mg, 2.84 mmol,
2.5 equiv) were reacted according to the general procedure
(reflux time 12 h). After column chromatography (silica
gel, petroleum ether/ether¼20:1), 3m could be isolated as
a yellow solid (211.4 mg, 55%); Rf¼0.28. 1H NMR
(250 MHz, CDCl3): d¼4.00 (s, 3H, OCH3), 7.13 (d,
3J¼9 Hz, 1H, Ar), 7.48 (d, 4J¼2 Hz, 1H, Ar), 7.61 (d,
3
3H, OCH3), 7.08 (d, J¼9 Hz, 1H, Ar), 7.17 (s, 1H, Ar),
3
4
7.21 (s, 1H, Ar), 7.83 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar),
8.26 (d, 4J¼2 Hz, 1H, Ar), 11.20 (s, 1H, OH), 11.94 (s, 1H,
OH). 13C NMR (50.3 MHz, CDCl3): d¼15.6, 20.5 (CH3),
52.7 (OCH3), 112.1 (C, Ar), 117.6 (CH, Ar), 118.0, 127.0,
127.3, 129.5 (C, Ar), 130.2, 132.3, 136.6, 138.2 (CH, Ar),
159.3, 164.4, 170.0 (COH, COOR), 199.3 (CO). IR (KBr,
cmꢁ1): ~n¼3148 ðwÞ, 2960 (w), 2363 (w), 1688 (s), 1624
(s), 1585 (s), 1440 (m), 1356 (s), 1289 (s), 1214 (s), 1091
(m), 798 (m), 717 (w). MS (70 eV, EI): m/z (%)¼300 [M+]
(40), 148 (100), 120 (29). HRMS (EI, 70 eV): calcd for
C17H16O5 (M+): 300.0998; found: 300.0998ꢂ3 ppm.
3
4
4J¼2 Hz, 1H, Ar), 7.85 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar),
8.27 (d, 4J¼2 Hz, 1H, Ar), 11.33 (s, 1H, OH), 12.10–12.20
(br s, 1H, OH). 13C NMR (50.3 MHz, CDCl3): d¼52.9
(OCH3), 112.4 (C, Ar), 118.3 (CH, Ar), 120.3, 123.3,
124.14, 127.9 (C, Ar), 130.3, 132.6, 135.6, 136.6 (CH, Ar),
157.2, 165.2, 169.8 (COH, COOR), 197.6 (CO). IR (KBr,
cmꢁ1): ~n¼3103 ðwÞ, 3077 (w), 2958 (w), 2927 (w), 1693
(s), 1580 (m), 1437 (s), 1356 (s), 1299 (s), 1222 (s), 1089
(w), 801 (w). MS (70 eV, EI): m/z (%)¼342 ([M+], 37Cl,
35Cl) (57), 340 ([M+], 35Cl, 35Cl) (87), 190 (54), 188 (83),
152 (86), 147 (58), 120 (100). HRMS (EI, 70 eV): calcd for
C15H10Cl2O5 (M+): 339.9905; found: 339.9905ꢂ3 ppm.
3.2.11. 5-(5-Chloro-2-hydroxybenzoyl)-2-hydroxybenz-
oic acid methyl ester (3k). Phosphorane 2c (492.3 mg,
1.31 mmol, 1.3 equiv), formylchromone 1f (209.2 mg,
1.00 mmol) and NaH (83.2 mg, 3.47 mmol, 3.5 equiv)
were reacted according to the general procedure (reflux
time 4 h). After column chromatography (silica gel, petro-
leum ether/ether¼20:1), 3k could be isolated as a yellow
solid (154.4, 50%); Rf¼0.25. 1H NMR (250 MHz, CDCl3):
3.2.14. 5-(3,5-Dibromo-2-hydroxybenzoyl)-2-hydroxy-
benzoic acid methyl ester (3n). Phosphorane 2c
(488.5 mg, 1.30 mmol, 1.3 equiv), formylchromone 1i
(329.2 mg, 0.99 mmol) and NaH (97.7 mg, 4.07 mmol,
4.1 equiv) were reacted according to the general procedure
(reflux time 14 h). After column chromatography (silica
gel, petroleum ether/ether¼1:2), 3n could be isolated as
3
d¼4.00 (s, 1H, OCH3), 7.04 (d, J¼9 Hz, 1H, Ar), 7.12 (d,
3
4
3J¼9 Hz, 1H, Ar), 7.46 (dd, J¼9 Hz, J¼3 Hz, 1H), 7.53
4
3
4
(d, J¼3 Hz, 1H, Ar), 7.84 (dd, J¼9 Hz, J¼2 Hz, 1H,
4
Ar), 8.27 (d, J¼2 Hz, 1H, Ar), 11.27 (s, 1H, OH), 11.69
(s, 1H, OH). 13C NMR (50.3 MHz, CDCl3): d¼52.8
(OCH3), 112.3 (C, Ar), 118.1 (CH, Ar), 119.7 (C, Ar),
120.2 (CH, Ar), 123.5, 128.4 (C, Ar), 131.8, 132.4, 136.0,
136.5 (CH, Ar), 161.4, 164.9, 169.9 (COH, COOR), 197.9
(CO). IR (KBr, cmꢁ1): ~n¼3430 ðmÞ, 3180 (w), 3116 (w),
1680 (s), 1627 (s), 1583 (s), 1467 (s), 1356 (s), 1291 (s),
1207 (s), 1089 (m), 794 (m), 643 (m). MS (70 eV, EI): m/z
(%)¼306 ([M+], 35Cl) (100), 155 (51), 154 (67), 147 (38),
120 (51). Anal. Calcd for C15H11O5Cl (306.70): C, 58.74;
H, 3.62. Found: C, 58.60; H, 3.54.
1
a yellow solid (170.9 mg, 51%); Rf¼0.12–0.39. H NMR
3
(300 MHz, pyridine-d5): d¼7.19 (d, J¼12 Hz, 1H, Ar),
7.80 (d, 4J¼2 Hz, 1H, Ar), 7.97 (d, 4J¼2 Hz, 1H, Ar), 8.07
3
4
4
(dd, J¼12 Hz, J¼2 Hz, 1H, Ar), 8.91 (d, J¼2 Hz, 1H,
Ar), 11.80–12.10 (m, 3H, 2ꢃOH, COOH). 13C NMR
(75.5 MHz, pyridine-d5): d¼111.3, 114.4, 116.6 (C, Ar),
117.9 (CH, Ar), 127.9, 128.67 (C, Ar), 132.6, 134.5,
136.2, 138.5 (CH, Ar), 154.9, 167.5, 174.2 (COH, COOH),
194.6 (CO). IR (KBr, cmꢁ1): ~n¼3430 ðmÞ, 3067 (w),
1625 (m), 1584 (m), 1425 (m), 1319 (m), 1223 (m), 1178
(m), 784 (m), 756 (m), 694 (m), 634 (m). MS (EI, 70 eV):
m/z (%)¼416 ([M+], 79Br, 81Br) (52), 280 (54), 279 (79),
278 (100), 276 (51), 147 (77), 121 (82), 120 (54).
3.2.12. 5-(5-Bromo-2-hydroxybenzoyl)-2-hydroxybenz-
oic acid methyl ester (3l). Phosphorane 2c (458.9 mg,
1.22 mmol, 1.3 equiv), formylchromone 1g (236.1 mg,
0.93 mmol) and NaH (58.8 mg, 2.45 mmol, 2.6 equiv)
were reacted according to the general procedure (reflux
time 4 h). After column chromatography (silica gel, petro-
leum ether/ether¼20:1), 3l could be isolated as a yellow
solid (182.3 mg, 56%); Rf¼0.28. 1H NMR (250 MHz,
CDCl3): d¼4.00 (s, 1H, OCH3), 6.99 (d, 3J¼9 Hz, 1H,
3.2.15. 5-(5-Chloro-2-hydroxy-4-methylbenzoyl)-2-
hydroxybenzoic acid methyl ester (3o). Phosphorane 2c
(436.5 mg, 1.16 mmol, 1.3 equiv), formylchromone 1j
(195.3 mg, 0.88 mmol) and NaH (77.4 mg, 3.23 mmol,
3.7 equiv) were reacted according to the general procedure
(reflux time 5 h). After column chromatography (silica gel,
petroleum ether/ether¼20:1), 3o could be isolated as a
3
3
4
Ar), 7.12 (d, J¼9 Hz, 1H, Ar), 7.59 (dd, J¼9 Hz, J¼
2 Hz, 1H, Ar), 7.61 (d, 4J¼2 Hz, 1H, Ar), 7.84 (dd,
3J¼9 Hz, J¼2 Hz, 1H, Ar), 8.27 (d, J¼2 Hz, 1H, Ar),
4
4

E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
3299
yellow solid (135.5 mg, 48%); Rf¼0.32. 1H NMR
(250 MHz, CDCl3): d¼2.40 (s, 3H, CH3), 3.99 (s, 3H,
Spectroscopic data of 5a: 1H NMR (CDCl3, 250 MHz, keto/
enol¼1:2): d¼1.31 (t, 3J¼7 Hz, 3H, CH3), 2.28 (s, 3H,
CH3), 3.75 (s, 3H, CH3), 4.25 (q, 3J¼7 Hz, 2H, CH2), 5.25
(s, 1H, CH), 6.78 (s, 1H, CH), 11.99 (s, 1H, CH). 13C
NMR (CDCl3, 75 MHz): d¼14.2, 14.6 (CH3, keto, enol),
50.5 (CH2, keto), 51.5, 52.1 (CH3, keto, enol), 61.4, 61.8
(CH2, keto, enol), 95.8 (CH, enol), 130.5, 130.5 (CH, keto,
enol), 137.1, 143.6 (C), 167.3, 167.7, 169.4, 172.9, 193.0
(CO, keto, enol). IR (KBr, cmꢁ1): ~n¼2968 ðwÞ, 2955 (w),
1714 (s), 1651 (s), 1589 (s), 1448 (s). MS (EI, 70 eV): m/
z¼214 (M+, 9), 182 (7), 169 (8), 141 (100), 137 (20).
HRMS (EI, 70 eV): calcd for C10H14O5 (M+) m/z
(%)¼214.0841; found: 214.0841ꢂ2 ppm.
3
OCH3), 6.96 (s, 1H, Ar), 7.10 (d, J¼9 Hz, 1H, Ar), 7.52
3
4
(s, 1H, Ar), 7.82 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar), 8.24 (d,
4J¼2 Hz, 1H, Ar), 11.25 (s, 1H, OH), 11.73 (s, 1H, OH).
13C NMR (50.3 MHz, CDCl3): d¼20.8 (CH3), 52.8
(OCH3), 112.2, 117.9 (C, Ar), 118.0, 120.5 (CH, Ar),
124.1, 128.6 (C, Ar), 132.16, 132.24, 136.4 (CH, Ar),
145.4 (C, Ar), 161.4, 164.7, 169.9 (COH, COOR), 197.6
(CO). IR (KBr, cmꢁ1): ~n¼3109 ðmÞ, 3068 (m), 1676 (s),
1629 (s), 1581 (s), 1441 (s), 1357 (s), 1328 (s), 1214 (s),
1208 (s), 794 (s). MS (70 eV, EI): m/z (%)¼320 ([M+],
35Cl) (75), 169 (61), 168 (100). HRMS (EI, 70 eV): calcd
for C16H13ClO5 (M+): 320.0451; found: 320.0451ꢂ3 ppm.
3.4.2. (2E,4Z)-1,6-Diethoxy-4-hydroxy-2-methyl-1,6-
dioxo-2,4-hexadiene (5b). Procedure A: Starting with phos-
phorane 2b (0.390 g, 1.0 mmol) and ethyl pyruvate (0.232 g,
2.0 mmol), 5b was isolated (0.181 g, 80%) as a colourless
oil.
3.2.16. 5-(5-Nitro-2-hydroxybenzoyl)-2-hydroxybenzoic
acid methyl ester (3p). Phosphorane 2c (466.4 mg,
1.24 mmol, 1.4 equiv), formylchromone 1k (201.8 mg,
0.92 mmol) and NaH (77.8 mg, 3.24 mmol, 3.5 equiv)
were reacted according to the general procedure (reflux
time 4 h). After column chromatography (silica gel, petro-
leum ether/ether¼5:1), 3p could be isolated as a white solid
(46.2 mg, 16%); Rf¼0.21. 1H NMR (250 MHz, CDCl3):
d¼4.00 (s, 3H, OCH3), 7.17 (d, 3J¼9 Hz, 1H, Ar), 7.19 (d,
Procedure B: Starting with phosphoran 2b (0.780 g,
2.0 mmol) and ethyl pyruvate (0.116 g, 1.0 mmol), dis-
solved in benzene (10 mL), 5b was isolated (0.115 g, 50%)
as a colourless oil.
3
4
3J¼9 Hz, 1H, Ar), 7.90 (dd, J¼9 Hz, J¼2 Hz, 1H, Ar),
4
3
4
8.30 (d, J¼2 Hz, 1H, Ar), 8.40 (dd, J¼9 Hz, J¼3 Hz,
Keto/enol¼1:1. IR (KBr, cmꢁ1): ~n¼2985 ðwÞ, 1791 (m),
1717 (s), 1653 (s), 1592 (m), 1427 (m). UV–vis/NIR
(MeCN): lmax(lg 3)¼291.70 (4.07) nm.
4
1H, Ar), 8.58 (d, J¼3 Hz, 1H, Ar), 11.37 (s, 1H, OH),
12.30–12.60 (br s, 1H, OH). 13C NMR (50.3 MHz,
CDCl3): d¼52.9 (CH3), 112.5, 117.9 (C, Ar), 118.7, 119.6
(CH, Ar), 127.5 (C, Ar), 128.9, 130.7, 132.7, 136.5 (CH,
Ar), 139.4 (C, Ar), 165.5, 167.8, 169.7 (COH, COOR),
197.75 (CO). IR (KBr, cmꢁ1): ~n¼3434 ðmÞ, 3236 (m),
2923 (m), 2852 (m), 1699 (s), 1632 (s), 1576 (s), 1477 (s),
1345 (s), 1241 (s), 1199 (s), 1098 (m), 677 (m), 640 (m).
MS (70 eV, EI): m/z (%)¼317 [M+] (100), 285 (43), 152
(24), 147 (28), 120 (52). HRMS (EI, 70 eV): calcd for
C15H11NO7 (M+): 317.0536; found: 317.0536ꢂ3 ppm.
3.4.3. (2E,4Z)-1-Ethoxy-4-hydroxy-2-methyl-1,6-dioxo-
6-piperidyl-2,4-hexadiene (5c). Procedure B: Starting
with phosphorane 2e (0.866 g, 2.0 mmol) and ethyl pyruvate
(0.232 g, 2.0 mmol), dissolved in toluene (10 mL), 5c was
isolated (0.254 g, 48%) as a colourless oil. 1H NMR
(CDCl3, 300 MHz, keto/enol¼1:2): d¼1.24 (t, 3J¼7 Hz,
3H, CH3), 1.51–1.62 (m, 6H, CH2), 3.43–3.51 (m, 4H,
3
CH2), 4.16 (q, J¼7 Hz, 2H, CH2), 5.38 (s, 1H, CH), 6.73
(s, 1H, CH), 14.75 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3): d¼14.1, 14.2, 14.4, 14.6 (CH3, keto, enol), 24.4,
24.48, 25.48, 26.3, 42.9, 47.5, 50.6, 61.2, 61.7 (CH2, keto,
enol), 93.6, 131.1, 132.4 (CH, keto, enol), 135.2, 142.6,
164.6, 167.3, 168.1, 169.2, 170.0, 195.1 (C, keto, enol). IR
(KBr, cmꢁ1): ~n¼2981 ðwÞ, 2939 (s), 2860 (m), 1711 (s),
1644 (s), 1588 (s), 1485 (s), 1447 (m). UV–vis/NIR
(MeCN): lmax(lg 3)¼313.42 (4.20) nm. MS (EI, 70 eV):
m/z¼267 (M+, 49), 194 (18), 127 (22), 111 (42), 84 (100).
HRMS (FT-ICR): calcd for C14H22NO4 m/z¼268.15433;
found: m/z¼268.15468.
3.3. General procedure A for the synthesis of 2-hydroxy-
1,3-hexadiene-1,4-dicarboxylates 5a–d
A suspension of phosphorane 2 and of ethyl pyruvate (4) was
stirred for 1 h at 80 ꢀC. After cooling to 20 ꢀC, the residue
was purified by chromatography (silica gel, n-hexane/
CH2Cl2¼1:1).
3.4. General procedure B for the synthesis of 2-hydroxy-
1,3-butadiene-1,4-dicarboxylates 5a–d
A benzene or toluene solution of phosphorane 2 and of ethyl
pyruvate (4) was refluxed for 5 h. After cooling to 20 ꢀC, the
solvent was removed in vacuo and the residue was purified
by chromatography (silica gel, n-hexane/CH2Cl2¼1:1).
3.4.4. (2E,5Z)-1-Ethoxy-6-hydroxy-2-methyl-1,6-dioxo-
6-phenyl-2,5-hexadiene (5d). Procedure B: Starting with
phosphorane 2g (0.633 g, 1.5 mmol) and ethyl pyruvate
(0.186 g, 1.6 mmol), dissolved in benzene (8 mL), 5d was
isolated (0.126 g, 49%) as a colourless solid. 1H NMR
3
3.4.1. (2E,4Z)-1-Ethoxy-6-methoxy-4-hydroxy-2-methyl-
1,6-dioxo-2,4-hexadiene (5a). Procedure A: Starting with
phosphorane 2c (0.376 g, 1.0 mmol) and ethyl pyruvate
(0.232 g, 2.0 mmol), 5a was isolated (0.163 g, 76%) as a
colourless oil.
(CDCl3, 300 MHz, keto/enol <2:98): d¼1.34 (t, J¼7 Hz,
3
3H, CH3), 2.34 (s, 3H, CH3), 4.27 (q, J¼7 Hz, 2H, CH3),
6.36 (s, 1H, CH), 6.96 (s, 1H, CH), 7.44–7.58 (m, 3H,
3
CH), 7.92 (d, J¼7 Hz, 2H, CH), 16.09 (br s, 1H, OH).
13C NMR (75 MHz, CDCl3): d¼14.6, 15.2 (CH3), 61.9
(CH2), 101.3, 127.9, 129.1, 132.0, 133.3 (CH), 140.0,
167.6, 179.6, 190.1 (C). IR (KBr, cmꢁ1): ~n¼2983 ðwÞ,
1716 (s), 1684 (m), 1641 (s), 1599 (s), 1571 (s), 1456 (s).
UV–vis/NIR (MeCN): lmax(lg 3)¼344.20 (4.20) nm. MS
Procedure B: Starting with phosphorane 2c (1.81 g,
4.8 mmol) and ethyl pyruvate (0.464 g, 4.0 mmol), dis-
solved in benzene (40 mL), 5a was isolated (0.426 g, 50%).

3300
E. Holtz et al. / Tetrahedron 63 (2007) 3293–3301
(EI, 70 eV): m/z¼260 (M+, 8), 187 (30), 146 (17), 121 (9),
105 (47). Anal. Calcd for C14H14O4: C, 68.28; H, 5.74.
Found: C, 67.87; H, 5.52.
3. (a) Liou, J.-P.; Chang, J.-Y.; Chang, C.-W.; Chang, C.-Y.;
Mahindroo, N.; Kuo, F.-M.; Hsieh, H.-P. J. Med. Chem.
2004, 47, 2897; (b) Liou, J.-P.; Chang, C.-W.; Song, J. S.;
Yang, Y. S.; Yeh, C. F.; Tseng, H. Y.; Lo, Y. K.; Chang, C.-L.;
Chang, C.-M.; Hsieh, H.-P. J. Med. Chem. 2002, 45, 2556.
4. Appel, B.; Rotzoll, S.; Reinke, H.; Langer, P. Eur. J. Org. Chem.
2006, 3638.
3.5. General procedure for the synthesis of buta-2,4-
diene-1,6-dicarboxylates 8a,b
5. Cai, X.; Sakamoto, M.; Fujitsuka, M.; Majima, T. Chem.—Eur.
J. 2005, 11, 6471 and references cited therein.
6. Langhals, H.; Fuchs, K. Chem. Unserer Zeit 2004, 38, 98 and
references cited therein.
7. For the SmI2 mediated reaction of benzaldehydes with benzyl-
halides and subsequent oxidation, see: Shiue, J.-S.; Lin, M.-H.;
Fang, J.-M. J. Org. Chem. 1997, 62, 4643.
8. Buchta, E.; Egger, H. Chem. Ber. 1957, 90, 2760.
9. Langer, P.; Schneider, T. Synlett 2000, 497.
10. Langer, P.; Holtz, E. Synlett 2003, 402.
11. For reactions of 3-formylchromones, see: (a) Nohara, A.;
Umetani, T.; Sanno, Y. Tetrahedron 1974, 30, 3553; (b)
Jones, W. D.; Albrecht, W. L. J. Org. Chem. 1976, 41, 706;
the cyclization of 3-formylchromones with formamidine and
amidines afforded 5-(2-hydroxybenzoyl)-pyrimidines: (c)
A CH2Cl2 suspension of phosphorane 2, ethyl 2-hydroxy-
acetate (6) and MnO2 was stirred for 16 h at 20 ꢀC. The sus-
pension was filtered and the filtrate was concentrated in
vacuo. The residue was purified by chromatography (silica
gel, n-hexane/CH2Cl2¼1:1).
3.5.1. (2Z,4E)-6-Ethoxy-1-methoxy-3-hydroxy-1,6-
dioxo-2,4-hexadiene (8a). Starting with phosphorane 2c
(0.376 g, 1.0 mmol), 6 (0.208 g, 2.0 mmol) and MnO2
(1.74 g, 20.0 mmol), dissolved in CH2Cl2 (20 mL), 8a was
isolated (0.104 g, 52%, keto/enol >2:98) as a colourless
1
3
oil. H NMR (CDCl3, 300 MHz): d¼1.29 (t, J¼7 Hz, 3H,
CH3), 3.76 (s, 3H, CH3), 4.22 (q, 3J¼7 Hz, 2H, CH2), 5.29
3
(s, 1H, CH), 6.61 (d, Jtrans¼16 Hz, 1H, CH), 6.90 (d,
3Jtrans¼16 Hz, 1H, CH), 11.56 (s, 1H, OH). IR (KBr,
cmꢁ1): ~n¼3436 ðsÞ, 2986 (w), 2956 (w), 1718 (s), 1663
(s), 1599 (s), 1452 (s), 1402 (w). UV–vis/NIR (MeCN):
lmax(lg 3)¼291.96 (4.13) nm. MS (EI, 70 eV): m/z¼200
(M+, 5), 155 (9), 127 (100), 123 (21), 99 (15). Anal. Calcd
for C9H12O5: C, 54.00; H, 6.04. Found: C, 54.42; H, 6.35.
€
Lowe, W. Synthesis 1976, 274; and (d) Petersen, U.; Heitzer,
H. Liebigs Ann. Chem. 1976, 1663; with enamines: (e)
Heber, D. Synthesis 1978, 691; with hydrazines: (f) Eiden, F.;
Haverland, H. Arch. Pharm. (Weinheim, Ger.) 1968, 301,
819; and (g) Ghosh, C. K.; Mukhopadhyay, K. K. J. Indian
Chem. Soc. 1978, 55, 386; with H2NOH$HCl: (h) Hsung,
R. P.; Zificsak, C. A.; Wei, L.-L.; Zehnder, L. R.; Park, F.;
Kim, M.; Tran, T.-T. T. J. Org. Chem. 1999, 64, 8736; with
o-phenylenediamine: (i) Ghosh, C. K.; Khan, S. Synthesis
1980, 701; for conversions into pyrroles and thiophenes: (j)
Fitton, A. O.; Frost, J. R.; Suschitzky, H.; Hougton, P. G.
Synthesis 1977, 133; for reactions with ketene acetals: (k)
Wallace, T. W.; Wardell, I.; Li, K.-D.; Leeming, P.;
Redhouse, A. D.; Challand, S. R. J. Chem. Soc., Perkin
Trans. 1 1995, 2293; with dienes: (l) Sandulache, A.; Silva,
A. M. S.; Cavaleiro, J. A. S. Tetrahedron 2002, 58, 105; for re-
actions of 3-formylchromone with C-nucleophiles, see: (m)
Ghosh, C. K.; Khan, S. Synthesis 1981, 903; (n) Hass, G.;
Stanton, J. L.; von Sprecher, A.; Wenk, P. J. Heterocycl.
Chem. 1981, 18, 607; (o) Prousek, J. Collect. Czech. Chem.
Commun. 1991, 1361; (p) Ghosh, C. K.; Bandyopadhyay, C.;
Biswas, S.; Chakravarty, A. K. Indian J. Chem., Sect. B
1990, 29, 814; (q) Bandyopadhyay, C.; Sur, K. R.; Patra, R.
J. Chem. Res., Synop. 1998, 12, 802; for a review on 3-formyl-
chromones, see: (r) Ellis, G. P. The Chemistry of Heterocyclic
Compounds; Weisberger, A., Ed.; Interscience: New York, NY,
1977; Vol. 35, p 921.
3.5.2. (2Z,4E)-1,6-Diethyl-3-hydroxy-2,4-hexadiene-1,6-
dicarboxylate (8b). Starting with phosphorane 2b
(0.390 g, 1.0 mmol), 6 (0.208 g, 2.0 mmol) and MnO2
(1.74 g, 20.0 mmol), dissolved in CH2Cl2 (20 mL), 8b was
isolated (0.110 g, 51%, keto/enol >2:98) as a colourless
oil. 1H NMR (300 MHz, CDCl3): d¼1.15–1.34 (m, 6H,
CH3), 4.15–4.29 (m, 4H, CH2), 5.29 (s, 1H, CH), 6.64 (d,
3
3J¼16 Hz, 1H, CH), 6.91 (d, J¼16 Hz, 1H, CH), 11.66
(s, 1H, OH). 13C NMR (75 MHz, CDCl3): d¼14.1, 14.2
(CH3), 60.8, 61.0 (CH2), 96.6, 125.8, 137.3 (CH), 165.9,
166.0, 172.0 (C). MS (EI, 70 eV): m/z¼214 (M+, 12), 169
(22), 141 (100), 127 (44), 112 (64). HRMS (EI, 70 eV):
calcd for C10H14O5 (M+): 214.0841; found: m/z
(%)¼214.0841ꢂ2 ppm. IR (KBr, cmꢁ1): ~n¼3106 ðwÞ,
2985 (m), 2940 (w), 2912 (w), 1722 (s), 1695 (w), 1659
(s), 1600 (s), 1470 (w), 1448 (w), 1423 (m). UV–vis/NIR
(MeCN): lmax(lg 3)¼292.79 (4.23) nm.
Acknowledgements
12. For cyclization reactions phosphorane 2b, see for example: (a)
Hatanaka, M.; Tanaka, Y.; Ueda, I. Tetrahedron Lett. 1995,
3719; (b) Banwell, M. G.; Cameron, J. M. Tetrahedron Lett.
1996, 525; (c) Hatanaka, M.; Ishida, A.; Tanaka, Y.; Ueda, I.
Tetrahedron Lett. 1996, 401; (d) Ceccarelli, S.; Piarulli, U.;
Gennari, C. Tetrahedron Lett. 1999, 153.
We are grateful to Dr. M. Noltemeier for X-ray crystal
structure analyses. Financial support from the Fonds
der Chemischen Industrie e. V. and from the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
References and notes
13. For cyclization reactions of phosphoranes 2 from our labora-
tory, see: (a) Langer, P.; Kracke, B. Synlett 2001, 1790; (b)
Holtz, E.; Langer, P. Synlett 2004, 1805.
14. CCDC-617111 (3e) and CCDC-617112 (3o) contain all crys-
tallographic details of this publication and is available
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.
html or can be ordered from the following address: Cam-
bridge Crystallographic Data Centre, 12 Union Road,
1. For salicylic esters and salicylic glycosides (e.g., salicortin),
see for example: Ro€mpp Lexikon Naturstoffe; Steglich, W.,
Fugmann, B., Lang-Fugmann, S., Eds.; Thieme: Stuttgart,
1997.
2. Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.; Boyd,
M. R.; Hamel, E.; Pettit, R. K. J. Med. Chem. 1998, 41, 1688.

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GB-Cambridge CB21EZ; fax: +44 1223 336 033; or deposit@
ccdc.cam.ac.uk.
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