Synthesis and characterization of low generation halogenated linear poly(arylpropargyl)ether (PAPE) branches via selective palladium catalyzed coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2005.10.110

A rapid convergent synthesis of first- and second-generation halogenated linear poly(arylpropargyl ether) branches 7 and 10 is described. The key step of the sequence studied involves a selective Sonogashira-Linstrumelle (S-L) cross-coupling reaction of a

Full text of DOI:10.1016/j.tetlet.2005.10.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8987–8991
Synthesis and characterization of low generation halogenated
linear poly(arylpropargyl)ether (PAPE) branches via
selective palladium catalyzed coupling reactions
Nathalie LÕHermite, Jean-Franc¸ois Peyrat, Mouaˆd Alami* and Jean-Daniel Brion
Laboratoire de Chimie The´rapeutique, BioCIS-CNRS (UMR 8076), Universite´ Paris-Sud, Faculte´ de Pharmacie,
ˆ
rue J.B. Cle´ment 92296 Chatenay-Malabry Cedex, France
Received 26 September 2005; revised 19 October 2005; accepted 21 October 2005
Abstract—A rapid convergent synthesis of first- and second-generation halogenated linear poly(arylpropargyl ether) branches 7 and
10 is described. The key step of the sequence studied involves a selective Sonogashira–Linstrumelle (S–L) cross-coupling reaction of
aryl iodides with alkynes bearing an sp2-carbon–iodine bond. Application to the synthesis of functionalized first-generation
poly(arylpropargylether) stars having a benzene-1,3,5-tricarboxylic acid core has been realized.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Over the last 30 years, the palladium–copper-catalyzed
coupling reaction of terminal alkynes with organic
halides has been extensively used for the introduction
of an alkynyl moiety in organic molecules.1 This proce-
dure named Sonogashira–Linstrumelle (S–L) is of great
interest since the preparation of organometallic acetyl-
ide species is not required and allows a huge range of
functionalized 1-alkynes to couple chemoselectively
under very mild conditions. Although selective coupling
reactions of multiple halogenated aryl or heteroaryl
halides with terminal alkynes are now well documented,2
selective S–L coupling of aryl halides with arylalkynes
bearing an sp2-carbon–halogen bond has received little
attention. In most cases reported in the literature, excel-
lent selectivities were obtained when the coupling was
carried out between aryl iodides and alkynes bearing
an sp2-carbon–fluorine, carbon–chlorine or carbon–bro-
mine bond.3 However, to our knowledge, there is no
example of the coupling of aryl iodides with alkynes
bearing an sp2-carbon–iodide bond, probably because
of the difficulty to control the reactivity of the two car-
bon–iodine bonds during the oxidative addition step to
a palladium(0) species. Herein, we report the results of
this study aimed at the synthesis of low generation
poly(arylpropargylether) linear branches 2 suitable for
the preparation of functionalized, chemically well-
defined three-dimensional poly(arylpropargylether) stars
1. As there is no increase in the number of branches
from one generation to another, the term Ôhyper-
branched starsÕ seems to be more appropriate than the
term ÔdendrimerÕ to characterize our macromolecules 1.
As part of a research field concerning novel dendrimers
for drug delivery4 we have initiated a program on the
synthesis of low generation poly(arylpropargylether)5
stars 1 (Scheme 1). The construction of these macromole-
cules involves an anchoring step of branches 2 possess-
ing a primary alcohol function of variable chain length
with central cores derived from 1,3,5-benzene tricarbox-
ylic acid (3, X = OH). Each successive generation in the
synthesis of branches 2 allows the incorporation of an
arylpropargylether unit, in which the triple bond of
the non-conjugated heteroatom-containing flexible link-
age provides a focal point for further structural manip-
ulation. Furthermore, ramification, materialized by the
introduction of a para-substituted phenyl group, may
potentiate the interaction with an active drug depending
on the nature of the functionalities. A further particular-
ity of star macromolecules is the ease of 1H NMR anal-
ysis due to the absence of complicated multiplicity.
Keywords: Palladium; Copper; Alkyne; Halogenated poly(arylpropar-
Thus, the construction of these functionalized star
macromolecules 1 required a rapid and flexible method
gylether); Poly(arylpropargylether) stars.
*
Corresponding author. E-mail: mouad.alami@cep.u-psud.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.110

8988
N. LÕHermite et al. / Tetrahedron Letters 46 (2005) 8987–8991
CO Me
2
CO Me
2
n
MeO C
2
O
n
m
O
O
O
OMe
m
O
HO
O
O
m
O
O
n
OMe
2
m
n = 1, 2
m = 1, 2, 4
MeO
1
COX
X = Cl
X = OH
O
XOC
COX
3
MeO
n
CO Me
2
Scheme 1.
to prepare linear branches
2
bearing various
Grignard addition, Williamson alkylation and then
S–L coupling (Scheme 2). Following this synthetic
scheme, compounds 6, easily accessible starting from
the corresponding aldehydes 4 by a Grignard 1,2-addi-
tion followed by a Williamson propargylation, are char-
acterized by the presence of both a terminal alkyne
group and an sp2-carbon–halogen bond. These func-
tionalities are able to undergo auto-coupling processes
under the S–L reaction conditions. For the success of
hydroxyalkyne aryl substituents. To this end, we fo-
cused our attention on a straightforward approach
based on the use of aryl halides 7 and 10, which could
represent useful building blocks to introduce hydroxy-
alkyne moieties of various chain length by a palla-
dium–copper S–L coupling reaction. The synthesis of
the first- and second-generation of these branches
involves an iterative, three-step sequence based on
MeO
MeO
MeO
(b)
(c)
R
O
OH
O
7a X = Br R = COOMe
5a X = Br
5b X = I
7b X = Br R = CHO
6a X = Br
6b X = I
X
X
X
7c X = I
7d X = I
R = COOMe
R = CHO
MeO
(a)
(d)
(b)
from
7b or 7d
OH
(a)
O
X
CHO
8a X = Br
8b X = I
OMe
4a X = Br
4b X = I
CO2Me
X
MeO
MeO
(e)
(f)
O
O
6b
+ 7c
O
O
9a X = Br
9b X = I
10a X = Br
10b X = I
OMe
OMe
X
X
Scheme 2. Reagents and conditions: (a) p-MeOC6H4MgBr (2 equiv), THF, À40 ꢁC (5a: 94%, 5b: 91%, 8a: 84%, 8b: 89%); (b) NaH 60% (2 equiv),
BrCH2C„CH (2 equiv), THF-DMF (1:1 v/v), 20 ꢁC (6a: 90%, 6b: 92%, 9a: 77%, 9b: 77%); (c) ArI or ArBr (2 equiv), PdCl2(PPh3)2 (5 mol %), CuI
(10 mol %), Et3N, 60 ꢁC (7a: 74%, 7b: 63% without CuI, 7c: 80%, 7d: 73%); (d) 6a (1.5 equiv), 5b (1 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %),
Et3N, 60 ꢁC, 1 h (8a: 88%); (e) p-IC6H4CO2Me (2 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N, 60 ꢁC (10a: 64%, 10b: 58%); (f) 6b
(1.5 equiv), 7c (1 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N, 60 ꢁC, 1 h (10b: 24%, 11: 14%).

N. LÕHermite et al. / Tetrahedron Letters 46 (2005) 8987–8991
8989
this strategy, cross-coupling must be favored with re-
spect to auto-coupling. Since terminal alkynes react at
a higher rate with aryl iodides than with aryl bromides
we initially investigated the preparation of brominated
derivatives 7a–b and 10a.
An alternative and rapid approach to 10b based on a
one-step coupling of 7c (bearing a non-activated car-
bon–iodine bond compared to methyl 4-iodobenzoate)
with substrate 6b was also explored. To this end, a cou-
pling reaction was attempted under the similar condi-
tions described above (PdCl2(PPh3)2 (5 mol %) and
CuI (10%), Et3N, 60 ꢁC) but only gave a 24% yield of
iodinated second generation linear branch 10b together
with 14% of iodinated third generation linear branch
11 (Scheme 3). Despite the low yield of this transforma-
tion, it represents a rapid entry to 10b (overall yield 20%
in three steps from 4b compared to 24% overall yield in
six steps from 4b).
To avoid its auto-coupling, brominated alkyne 6a was
slowly added, at 80 ꢁC, to a solution containing methyl
4-iodobenzoate, PdCl2(PPh3)2 (5 mol %) and CuI
(10 mol %) in triethylamine. Under these conditions,
the S–L cross-coupling reaction occurred selectively on
the carbon–iodine bond and resulted in the formation
of brominated first generation 7a in good yield (74%).
Under similar conditions, coupling 6a with 4-bromo-
benzaldehyde allowed the formation of 7b with a lower
yield (52%) whereas in the absence of copper iodide6a
the yield of 7b increased to 63%.
We then studied the coupling reaction of iodinated lin-
ear chains 7c and 10b with various hydroxy-terminal
alkyne derivatives (Table 1). All the reactions were
conducted in triethylamine at 60 ꢁC in the presence of
PdCl2(PPh3)2 (5 mol %) and CuI (10 mol %). Iodinated
first generation 7c reacted with propargylic and homo-
propargylic alcohols with excellent yields (88–91%, en-
tries 1 and 2) and with hex-5-yn-1-ol with a lower
yield (49%, entry 3). Under similar conditions, the sec-
ond-generation of linear branch derivatives 2d–e were
obtained in good yields (77–81%, entries 4 and 5). This
synthetic scheme was successful and afforded five differ-
ent hydroxyl linear branches10 from only two iodinated
derivatives 7c and 10b. It should be noted that all
compounds synthesized including first- and second-
When starting from 7b, brominated higher generation
10a was obtained according to the three-step sequence
described above based on Grignard addition (8a:
84%), Williamson propargylation (9a: 77%) and S–L
coupling reaction (10a: 64%). It should be noted that
the intermediate 8a may be obtained in a one-step
sequence in good yield (88%) when the coupling is per-
formed between bromoalkyne 6a and iodo alcohol 5b.
Having in our hands brominated derivatives 7a and 10a,
we next studied the introduction of propargylic and
homopropargylic alcohol chains under S–L coupling
reactions to obtain linear branches 2. All our attempts
to perform such coupling reactions employing various
combinations6 of Pd/solvent/amine mixtures (e.g.,
Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(PhCN)2, Pd2(dba)3/
PPh3 or P(tBu)3, THF, DMF, dioxane, Et3N, Et2NH,
iPr2NH or piperidine with or without CuI) were how-
ever, unsuccessful. In most cases, starting materials were
recovered or degradation occurred. These difficulties in
obtaining 2 from brominated derivatives 7a and 10a
led us to explore coupling reactions with the correspond-
ing iodides 7c and 10b.
MeO
O
COOMe
MeO
O
11
O
Since the carbon–iodide bond is more reactive than the
corresponding bromide and in order to avoid auto-cou-
pling reactions, various conditions were examined for
performing selective alkynylation of activated aryl iod-
ides such as methyl 4-iodobenzoate or 4-iodobenzalde-
hyde with substrate 6b. It was found that when 6b was
added slowly to the reaction mixture containing acti-
vated aryl iodides7 in triethylamine at 60 ꢁC in the pres-
ence of PdCl2(PPh3)2 (5 mol %) and CuI (10%), the
cross-coupling reaction occurred selectively on the car-
bon–iodide bond of the activated aromatic ring afford-
ing iodinated first-generation derivatives 7c–d8 in 80%
and 73% yields, respectively.
OMe
I
Scheme 3.
Table 1. Synthesis of linear branches 2a
(2 equiv)
R
7c or 10b
2
5% PdCl2(PPh3)2, 10% CuI
Et3N, 60˚C, 1 to 2 h
Entry
Iodinated branch
R
2
Yieldb (%)
1
2
3
4
5
7c
7c
CH2OH
2a
2b
2c
2d
2e
91
88
49
81
77
To achieve the synthesis of iodinated second generation
10b, 7d was subjected to the iterative reaction sequence.
Grignard addition afforded 8b in 89% yield. Propargyl-
ation of the latter (9b: 77%) followed by coupling of
the resulting alkyne 9b with methyl 4-iodobenzoate
selectively gave iodinated second generation 10b in
58% yield.9
(CH2)2OH
(CH2)4OH
CH2OH
7c
10b
10b
(CH2)2OH
a All reactions were performed with 1-alkyne (2 equiv) in the presence
of PdCl2(PPh3)2 (5 mol %), CuI (10 mol %) in Et3N at 60 ꢁC.
b Yield of isolated products.

8990
N. LÕHermite et al. / Tetrahedron Letters 46 (2005) 8987–8991
2. For a recent review on coupling reactions with multiple
halogenated heterocycles, see: Schro¨ter, S.; Stock, C.;
Bach, T. Tetrahedron 2005, 61, 2245–2267.
generation derivatives 7, 10 and 2 were fully character-
ized using NMR spectroscopy (1H and 13C), mass spec-
trometry (electrospray ESI) and elemental analysis. As
1
3. For recent coupling, see: (a) Kamikawa, T.; Hayashi, T. J.
Org. Chem. 1998, 63, 8922–8925; (b) Nakamura, K.;
Okubo, H.; Yamaguchi, M. Synlett 1999, 549–550; (c)
Wu, T. Y. H.; Ding, S.; Gray, N. S.; Schultz, P. G. Org.
expected with these linear branches, the H NMR spec-
tra show signals corresponding to the different monomer
layers and the integration clearly indicates which gener-
ation is involved.
¨
¨
Lett. 2001, 3, 3827–3830; (d) Godt, A.; Unsal, O.; Roos,
M. J. Org. Chem. 2000, 65, 2837–2842; (e) Kabalka, G.
W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017–
8028; (f) McDonagh, A. M.; Powell, C. E.; Morall, J. P.;
Cifuentes, M. P.; Humphrey, M. G. Organometallics 2003,
22, 1402–1413; (g) Cacchi, S.; Fabrizi, G.; Parisi, L. M.
Org. Lett. 2003, 5, 3843–3846; (h) He, H.; Wu, Y. J.
Tetrahedron Lett. 2004, 45, 3237–3239.
After synthesis of linear branches 2, their attachment to
a chosen core was carried out. The first (2a–b) and the
second (2d) generation compounds were thus reacted
with 1,3,5-benzenetricarbonyl chloride under various
conditions11 including Et3N, pyridine or DMAP in
CH2Cl2 or toluene. Surprisingly, the above-mentioned
reaction conditions did not yield the desired first- and
second-generation poly(arylpropargylether) stars 1.
Inseparable mixtures of products were obtained, despite
running the reactions for longer times and at higher tem-
peratures. However, under Mitsunobu conditions, we
found for instance that the coupling of 2b with 1,3,5-
benzenetricarboxylic acid in the presence of DEAD
(4.2 equiv) and PPh3 (5.4 equiv) in THF for 2 h at
60 ꢁC afforded the first generation poly(arylpropargyl-
ether) stars 1a12 (n = 1 and m = 2) in good isolated yield
(62%). This PAPE star was characterized by classical
4. For reviews of dendrimer carriers for drug delivery see: (a)
Aulenta, F.; Hayes, W.; Rannard, S. Eur. Polym. J. 2003,
39, 1741–1771; (b) Patri, A. K.; Majoros, I. J.; Baker, J. R.,
Jr. Curr. Opin. Chem. Biol. 2002, 6, 466–471; (c) Cloninger,
M. J. Curr. Opin. Chem. Biol. 2002, 6, 742–748; (d) Chow,
H. F.; Mong, T. K. K.; Nongrum, M. F.; Wan, C. W.
´
Tetrahedron 1998, 54, 8543–8660; (e) Liu, M.; Frechet, J.
M. J. Pharm. Sci. Technol. Today 1999, 2, 393–401.
5. Polyarylether dendrimers were demonstrated to be suit-
able candidates for drug-delivery, see: Liu, M.; Kono, K.;
Frechet, J. M. J. J. Controlled Release 2000, 65, 121–131.
6. (a) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron
Lett. 1993, 34, 6403–6406; (b) Alami, M.; Linstrumelle, G.
Tetrahedron Lett. 1991, 32, 6109–6112; (c) Hundertmark,
T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett.
2000, 2, 1729–1731; (d) Soheili, A.; Albanez-Walker, J.;
Murry, A. J.; Dormer, P. G.; Hughes, D. L. Org. Lett.
2003, 5, 4191–4194; (e) Mori, A.; Kawashima, J.; Shi-
mada, T.; Suguro, M.; Hirabayashi, K. Org. Lett. 2000, 2,
2935–2937.
1
analytical methods including H, 13C NMR and mass
spectrometry.
In conclusion, we have succeeded in developing a conve-
nient route to low generation halogenated linear
poly(arylpropargylether) branches 7 and 10 based on
S–L selective coupling of activated aryl iodides with halo-
genated alkynes. Iodinated linear branches 7c–d and
10b were used successfully for the synthesis of various
hydroxyl linear branches 2, which can serve as building
blocks for the synthesis of chemically well-defined,
multi-dimensional poly(arylpropargylether) stars. Preli-
minary results demonstrated that Mitsunobu conditions
could be an alternative solution to classical acylation for
the preparation of functionalized first generation
poly(arylpropargylether) stars 1. Further investigation
of these macromolecules with regard to their biocompat-
ibility and cell cytotoxicity is in progress.
7. Under similar conditions, coupling of 6b with the corre-
sponding activated aryl bromides resulted exclusively in
auto-coupling of 6b.
8. Preparation and characterization of iodinated first gener-
ation 7c: To
a solution of methyl 4-iodobenzoate
(1.45 mmol, 381 mg), PdCl2(PPh3)2 (0.036 mmol, 25 mg)
and CuI (0.07 mmol, 14 mg) in freshly distilled Et3N
(5 mL) was slowly added, at 60 ꢁC, via a syringe pump
(addition time 1 h) a solution of iodinated alkyne 6b
(0.72 mmol, 275 mg) in Et3N (5 mL). The reaction mixture
was stirred at 60 ꢁC and monitored by TLC analysis until
complete consumption of terminal alkyne 6b (30 min)
before being concentrated in vacuo. The residue was
dissolved in AcOEt (15 mL), washed successively with
aqueous HCl (0.5 M), H2O (2 · 20 mL), dried over
Na2SO4 and concentrated under vacuum. Purification by
flash chromatography (cyclohexane/AcOEt 9:1, Rf = 0.23)
afforded pure 7c (0.57 mmol, 295 mg, 80%). IR 2950–2836,
1718, 1606, 1585, 1509 cmÀ1; 1H NMR (200 MHz, CDCl3)
d 3.78 (s, 3H), 3.91 (s, 3H), 4.36 (s, 2H), 5.59 (s, 1H), 6.87
(d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.25 (d,
J = 8.8 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.65 (d,
J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H); 13C NMR
(50 MHz, CDCl3) d 52.2, 55.2, 56.5, 81.1, 85.7, 88.1, 93.1,
114.0, 127.2, 128.7, 129.0, 129.4, 129.8, 131.6, 132.6, 137.4,
141.4, 159.4, 166.4; MS (ESI): m/z (%) = 579 (100), 535
(20) [M+Na]+; C25H21IO4 (512.05): calcd C 58.61, H 4.13;
found C 58.74, H 4.18.
Acknowledgements
The CNRS is gratefully thanked for support of this re-
search and the MNSER for a doctoral fellowship to
N.L. Thanks also to Dr. R. H. Dodd for improving
the English of the manuscript.
References and notes
1. (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–
49; (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetra-
hedron Lett. 1975, 16, 4467–4470; (c) Ratovelomanana, V.;
Linstrumelle, G. Tetrahedron Lett. 1981, 22, 315–318; (d)
For an excellent overview of palladium-catalyzed
alkynylation of organic halides appeared recently see:
Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979–
2018.
9. Compound 10b: IR 3000–2836, 1719, 1607, 1585,
1509 cmÀ1 1H NMR (200 MHz, CDCl3) d 3.73 (s, 3H),
;
3.74 (s, 3H), 3.87 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 5.60 (s,
1H), 5.64 (s, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.85 (d,
J = 8.6 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 7.24 (m, 4H),
7.33 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.47 (d,

N. LÕHermite et al. / Tetrahedron Letters 46 (2005) 8987–8991
8991
J = 8.4 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.97 (d,
J = 8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3) d 52.2,
55.2, 56.5, 80.8, 81.3, 85.2, 85.7, 86.4, 88.3, 93.1, 114.0,
121.7, 127.0, 128.7, 129.1, 129.4, 131.7, 131.8, 132.8, 137.4,
141.6, 142.2, 159.3, 166.3; MS (ESI): m/z (%) = 785 (100)
[M+Na]+; C42H35IO6 (762.15): calcd. C 66.15, H 4.63;
found C 65.52, H 4.75.
3H), 3.78 (s, 3H), 3.91 (s, 3H), 4.33 (s, 2H), 4.36 (s, 2H),
4.46 (s, 2H), 5.65 (s, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.87 (d,
J = 8.8 Hz, 2H), 7.31 (m, 12H), 7.48 (d, J = 8.8 Hz, 2H),
7.98 (d, J = 8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3) d
51.6, 52.2, 55.2, 56.5, 81.0, 81.3, 85.1, 85.5, 85.7, 86.4, 87.2,
88.2, 113.9, 121.6, 121.8, 127.0, 127.3, 128.8, 129.4, 129.8,
131.7, 131.8, 132.8, 132.9, 142.1, 142.2, 159.4, 166.4; MS
(ESI): m/z (%) = 708 (100) [M+NH4]+; C45H38O7
(690,26): calcd. C 78.24, H 5.54; found C 76.50, H 5.68.
Compound 2e: IR 3500, 3000–2800, 1720, 1608,
10. Selected characterization data of the first and second
generation linear branches.
1
Compound 2a: IR 3466, 2951, 1718, 1606, 1509 cmÀ1; H
NMR (200 MHz, CDCl3) d 1.80 (br s, 1H), 3.78 (s, 3H);
3.91 (s, 3H), 4.36 (s, 2H), 4.47 (s, 2H), 5.64 (s, 1H), 6.87
(d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.36 (d,
J = 8.8 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.47 (d,
J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H); 13C NMR
(50 MHz, CDCl3) d 51.4, 52.1, 55.2, 56.4, 81.3, 85.3, 85.6,
87.4, 88.2, 113.9, 121.7, 126.9, 127.2, 128.7, 129.4, 129.6,
131.6, 132.7, 142.0, 159.3, 166.4; MS (ESI): m/z (%) = 458
(5) [M+NH4]+, 251 (100); C28H24O5 (440,16): calcd. C
76.35, H 5.49; found C 74.19, H 5.60.
1510 cmÀ1 1H NMR (200 MHz, CDCl3) d 2.59 (t,
;
J = 6.2 Hz, 2H), 3.70 (m, 8H), 3.83 (s, 3H), 4.26 (s, 2H),
4.29 (s, 2H), 5.57 (s, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.79 (d,
J = 8.6 Hz, 2H), 7.31 (m, 14H), 7.90 (d, J = 8.2 Hz, 2H);
13C NMR (50 MHz, CDCl3) d 29.5, 52.0, 55.0, 56.3, 60.9,
80.9, 81.1, 81.9, 85.1, 85.5, 86.2, 86.5, 88.1, 113.7, 113.8,
121.7, 122.4, 126.8, 127.1, 128.6, 129.3, 129.6, 131.5, 131.6,
132.6, 132.8, 141.4, 141.9, 159.1, 159.2, 166.2; MS (ESI):
m/z (%) = 727 (100) [M+Na]+.
11. (a) Twyman, L. J.; Beezer, A. E.; Mitchell, J. C. J. Chem.
Soc., Perkin Trans. 1 1994, 407–411; (b) Wilson, E. R.;
Frankel, M. B. J. Org. Chem. 1985, 50, 3211–3212; (c)
Pan, Y.; Ford, W. T. J. Org. Chem. 1999, 64, 8588–
8593.
Compound 2b: IR 3504, 2951, 2361, 1718, 1606,
1509 cmÀ1 1H NMR (200 MHz, CDCl3) d 1.85 (br s,
;
1H), 2.67 (t, J = 6.2 Hz, 2H), 3.78 (s, 3H), 3.79 (t,
J = 6.2 Hz, 2H), 3.92 (s, 3H), 4.36 (s, 2H), 5.63 (s, 1H),
6.86 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.34 (d,
J = 8.8 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.47 (d,
J = 8.6 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H); 13C NMR
(50 MHz, CDCl3) d 23.8, 52.2, 55.3, 56.5, 61.2, 81.4, 82.3,
85.7, 86.4, 88.2, 113.9, 122.6, 127.0, 127.3, 128.8, 129.4,
129.7, 131.7, 132.9, 141.5, 159.4, 166.5; MS (ESI): m/z
(%) = 472 (20) [M+NH4]+, 455 (10) [M+H]+, 265 (100);
C29H26O5 (454,18): calcd. C 76.63, H 5.77; found C 74.60,
H 5.90.
1
12. Compound 1a: IR 2953, 2360, 1720, 1606, 1509 cmÀ1; H
NMR (200 MHz, CDCl3) d 2.86 (t, J = 6.8 Hz, 6H), 3.76
(s, 9H), 3.90 (s, 9H), 4.35 (s, 6H), 4.52 (t, J = 6.8 Hz, 6H),
5.62 (s, 3H), 6.85 (d, J = 8.8 Hz, 6H), 7.25 (d, J = 8.8 Hz,
6H), 7.33 (d, J = 8.8 Hz, 6H), 7.38 (d, J = 8.8 Hz, 6H),
7.46 (d, J = 8.4 Hz, 6H), 7.96 (d, J = 8.4 Hz, 6H), 8.9 (s,
3H); 13C NMR (50 MHz, CDCl3) d 20.0, 52.2, 55.2, 56.4,
63.4, 81.3, 82.2, 85.0, 85.6, 88.2, 113.9, 122.4, 127.0, 127.3,
128.7, 129.4, 129.7, 131.2, 131.6, 132.8, 134.8, 141.5, 159.3,
164.6, 166.4; MS (ESI): m/z (%) = 1537 (25) [M+NH4+]+,
275 (100).
Compound 2d: IR 3476, 2999–2850, 2360, 1720, 1607,
1
1585, 1509 cmÀ1; H NMR (200 MHz, CDCl3) d 3.77 (s,