Concave reagents, 45.1 2,6-Di-tert-butylpyridine-loaded dendrimers and their use in vinyl triflate synthesis

Article abstract of DOI:10.1055/s-2005-865355

2,6-Di-tert-butyl-pyridine (DTBP) has been connected with dendrons and dendrimers of the Frechet type. Four dendrimers, both first and second generation derivatives have been synthesized and used as non-nucleophilic, recyclable bases in the formation of cyclohexenyl-1-triflate from cyclohexanone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865355

PAPER
1383
Concave Reagents, 45.1 2,6-Di-tert-butylpyridine-Loaded Dendrimers and
Their Use in Vinyl Triflate Synthesis
2
, 6-Di-tert-butylpy
l
ridine-
r
L
oade
d
i
D
endr
i
c
mers h Lüning,* Torsten Marquardt
Institut für Organische Chemie, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, 24098 Kiel, Germany
Fax +49(431)8801558; E-mail: luening@oc.uni-kiel.de
Received 5 February 2005
Dedicated to Prof. Dr. Bernd Giese on the occasion of his 65th birthday
Abstract: 2,6-Di-tert-butyl-pyridine (DTBP) has been connected
with dendrons and dendrimers of the Fréchet type. Four dendrimers,
both first and second generation derivatives have been synthesized
and used as non-nucleophilic, recyclable bases in the formation of
cyclohexenyl-1-triflate from cyclohexanone.
Keywords: steric hindrance, dendrimers, triflate, base catalysis, re-
cycling
Palladium-catalyzed cross-coupling reactions (e.g., Suzu-
ki, Stille, Heck, Sonogashira) have become more and
more important in organic synthesis.2,3 Besides halogenat-
ed compounds, aryl, and vinyl triflates are also valuable
Scheme 1
starting materials. A one step synthesis of vinyl triflates
developed by Stang4 requires 2,6-di-tert-butylpyridine
(DTBP, 2a) or its 4-methyl derivative 2b as a sterically
hindered, non-nucleophilic base (Figure 1). With triflic
anhydride (Tf2O), standard bases like pyridine form salts
such as 1 and thus lead to heterogeneous reaction mix-
tures. When using nucleophilic tertiary bases such as py-
ridine, the triflated quarternary ions such as 1 become the
triflating agents, while the use of DTBPs 2 leaves Tf2O as
the triflating agent.5
An alternative to polymer bound reagents are dendrimers
loaded with reagents.6–8 In relation to sterically hindered
bases, concave pyridines9,10 have been connected11,12 with
Fréchet-type dendrimers. Following this route, it should
be possible to connect DTBPs 2 to a Fréchet-type den-
drimer by an analogous synthesis.
Starting from 2,6-di-tert-butyl-4-methyl-pyridine13 (2b),
the methyl group was functionalized by NBS bromination
to give bromide 2d in 70% yield.14 Slightly more than two
equivalents of 2d were then reacted with 3,5-dihydroxy-
benzyl alcohol (5) to give the branched DTBP dimer 6 in
77% yield; the same reaction conditions were chosen as
those established for the dendrimer synthesis of the con-
cave pyridines (anhydrous acetone, K2CO3, 18-C-6).11,12
The hydroxy group of 6 was then exchanged for a bromine
atom, using tetrabromomethane triphenylphosphine, to
give 7 in 87% yield, ready for further elaboration into den-
drimers (Scheme 2).
Figure 1
Using DTBP 2b as base,4 cyclohexenyl-1-triflate (4) can
be synthesized in 76% yield starting from cyclohexanone
(3) and Tf2O (Scheme 1).
Starting from the bromo-substituted DTBP dimer 7, four
dendrimers, both first- and second-generation 10, 11, 14,
and 15 have then been synthesized. Reaction of the bro-
mide 7 with the diphenol 8 or the triphenol 9 in acetone
using potassium carbonate and 18-crown-6 gave first-
generation dendrimers 10 and 11 in 81% and 72% yield,
respectively (Scheme 3).
In this reaction, the base 2b has to be used in at least
equimolar quantities, and it is expensive. Therefore a
polymer-bound version 2c had been developed5 but disap-
pointingly, a lower yield (57%) and the formation of a
dimeric side product 16 (Scheme 5) were observed (18%).
The reaction of two equivalents of the bromide 7 with 3,5-
dihydroxybenzyl alcohol (5) in anhydrous acetone using
potassium carbonate and 18-crown-6 resulted in second-
generation dendrons, first as the hydroxy derivative 12
(58% yield), which was then brominated to give 84% of
SYNTHESIS 2005, No. 9, pp 1383–1388
x
x
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x
x
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5
Advanced online publication: 02.05.2005
DOI: 10.1055/s-2005-865355; Art ID: C00305SS
© Georg Thieme Verlag Stuttgart · New York

1384
U. Lüning, T. Marquardt
PAPER
hexenyl-1-triflate (4) from cyclohexanone (3) and Tf2O
was carried out as described in the literature.4 Table 1
compares the yields of 4 when different DTBPs were
used, including the dendrimers 10, 11, 14, and 15.
In contrast to the polymer 2c, DTBP 2b and all dendritic
DTBPs 10, 11, 14, and 15 produced the vinyl triflates 4 in
70–76% yield, and no dimeric side product 16 was found.
The dendritic DTBPs 10, 11, 14, and 15 could be recov-
ered in yields of up to 90% (see Experimental, Table 2).
Thus they offer an alternative to the single use of expen-
sive 2b, and in contrast to the polymer bound DTBP 2c,
they give the desired triflate 4 in yields comparable to 2b.
Melting points were determined on a Büchi hot-stage apparatus and
are uncorrected. IR spectra were recorded on a Perkin-Elmer Para-
gon FT-IR-spectrometer. 1H NMR spectra were recorded in CDCl3
or CCl4 solutions on Bruker AC 200 (200 MHz) and AM 300 (300
MHz) spectrometers with TMS as internal standard. 13C NMR spec-
tra were recorded at 50 MHz or 75 MHz on a Bruker AC 200 or AM
300 with CDCl3 or CCl4 as solvent using the TMS carbon signal as
internal standard. Mass spectra (EI or CI) were obtained on a Finni-
gan MAT 44S. MALDI spectra were recorded on a Bruker Biflex
III instrument. Analytical TLC was performed on commercial
Merck plates coated with silica gel GF254 (0.25 mm thick). Column
chromatography was performed on silica gel, Merck Kieselgel
(0.063–0.2 mm). Size-exclusion chromatography (GPC) was carried
out with a Waters 510 HPLC pump and a Waters 486 tunable UV-
detector; data analysis was performed with Millennium 2000 soft-
Scheme 2
Scheme 3
the bromide 13 using tetrabromomethane and triphe-
nylphosphine (Scheme 4).
This dendron 13 was then reacted with core molecules, the
diphenol 8 and the triphenol 9, using conditions as dis-
cussed for the first-generation dendrimers. Thus, two sec-
ond-generation dendrimers 14 and 15 could be
synthesized in 63% and 58% yield, respectively
(Scheme 5).
These second-generation dendrimers 14 and 15 carry up
to twelve DTBP units on their surface and possess a mo-
lecular weight of up to 3845 g/mol which was verified by
MALDI-MS. The dendrimers could be isolated in 100 mg
batches. Spectroscopy as well as microanalyses showed
no inclusion of solvent.
Application in Vinyl Triflate Synthesis
To test the ability of the DTBP-loaded dendrimers 10, 11,
14, and 15 to act as shielded bases, the synthesis of cyclo-
Scheme 4
Synthesis 2005, No. 9, 1383–1388 © Thieme Stuttgart · New York

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2,6-Di-tert-butylpyridine-Loaded Dendrimers
1385
Scheme 5
4-(Bromomethyl)-2,6-di-tert-butylpyridine (2d)
Table 1 Comparison of the Yields of Cyclohexenyl-1-triflate (4) in
the Reaction of Cyclohexanone (3) with Tf2O Using a Range of
DTBPs as Bases
NBS (3.6 g, 21 mmol) and AIBN (ca. 100 mg) were added to a so-
lution of 2,6-di-tert-butyl-4-methylpyridine (2b, 4 g, 20 mmol) in
anhyd CCl4 (200 mL). The solution was heated to reflux for 4 h.
During this time, AIBN (3 × ca. 100 mg) was added (after 1 h, 2 h,
and 3 h). When all NBS had reacted and only succinimide was float-
ing on the solution (there was no more insoluble NBS at the bottom
of the reaction vessel), the solid was filtered off and the solvent was
evaporated in vacuo. Distillation in vacuo gave 4 g (70%) of 2d as
a colorless oily liquid.
Base
Yield of 4 (%)
2b (4-Me-DTBP)
70, 764
575,a
74
2c (polymeric DTBP)
10 (1st-generation, 4 DTBPs)
11 (1st-generation, 6 DTBPs)
14 (2nd-generation, 8 DTBPs)
15 (2nd-generation, 12 DTBPs)
Bp 68 °C/0.02 Torr (Lit.14 94 °C/2 Torr).
72
IR (KBr): 2957, 2921, 2865 (CH), 1599 (Ar), 1479, 1416, 1360,
1249, 1219, 1164, 853, 698, 674 cm–1.
1H NMR (CCl4, 200 MHz): d = 1.37 [s, 18 H, C(CH3)3], 4.35 (s, 2
H, ArCH2Br), 7.08 (s, 2 H, PyH).
13C NMR (CCl4, 50 MHz): d = 30.4 [q, C(CH3)3], 37.8 [s, C(CH3)3],
40.0 (t, ArCH2Br), 115.4 [d, Py(C-3,5)], 140.9 [s, Py(C-4)], 168.5
[s, Py(C-2,6)].
74
75
a The dimer 16 was found in 18% yield besides the desired product 4.
MS (CI, isobutane): m/z (%) = 284 (100) [M+ + 1], 282 [M+ + 1]
(70), 204 (21), 100 (31).
Dendrons 6 and 12; General Procedure
A mixture of the (dendritic) benzylbromide 2d14 or 7 (2.1–2.4
equiv), 3,5-dihydroxybenzyl alcohol (5, 1.0 equiv), anhyd K2CO3
(2.5–3.0 equiv) and 18-C-6 (0.2–0.6 equiv) was heated to reflux un-
der nitrogen in anhyd acetone (100 mL). The progress of the reac-
tion was monitored by TLC, and the reaction was stopped after 4–8
d when no starting material could be detected, or when no further
conversion could be detected.
ware; column was from MZ laboratories (300 × 8 mm; pore size:
500 Å) with THF as solvent. Elemental analyses were carried out on
VarioEl, Elementaranalysensysteme GmbH. 2,6-Di-tert-butyl-4-
methylpyridine (2b) was synthesized according to the literature.13
All other starting materials were purchased and used without further
purification.
Synthesis 2005, No. 9, 1383–1388 © Thieme Stuttgart · New York

1386
U. Lüning, T. Marquardt
PAPER
After evaporation of the solvent, H2O (90 mL) and CH2Cl2 (30 mL)
were added, and the aqueous layer was extracted with CH2Cl2 (3–
5 × 20–100 mL). After drying with MgSO4 and evaporation of the
solvent in vacuo, the crude product was purified by chromatography
(200–500-fold excess of silica gel).
added and stirring was continued. The reaction was quenched by the
addition of a large excess of H2O (ca. 30 mL), and the aqueous layer
was extracted with CH2Cl2 (3–5 × 15–100 mL). The combined or-
ganic layer was dried with MgSO4, and after evaporation of the sol-
vent, the crude product was purified by chromatography (200–500-
fold excess of silica gel).
3,5-Bis(2,6-di-tert-butylpyridin-4-ylmethoxy)benzyl Alcohol (6)
According to the general procedure, 4-(bromomethyl)2,6-di-tert-
butylpyridine (2d, 650 mg, 2.28 mmol), 3,5-dihydroxybenzyl alco-
hol (5, 155 mg, 1.11 mmol), anhyd K2CO3 (336 mg, 2.44 mmol),
and 18-C-6 (58 mg, 0.20 mmol) were reacted for 3 d. Chromatogra-
phy (cyclohexane–Et2O, 2:1, Rf 0.2), gave 470 mg (77%) of 6 as a
colorless, glassy solid.
3,5-Bis(2,6-di-tert-butylpyridin-4-ylmethoxy)benzyl Bromide
(7)
According to the general procedure, 6 (2.6 g, 4.7 mmol), CBr4 (2.0
g, 6.0 mmol) and PPh3 (1.6 g, 6.0 mmol) were reacted for 30 min.
Chromatography (CH2Cl2–EtOH, 15:1; Rf 0.85) gave 2.6 g (87%) of
7 as a slightly yellow, glassy solid.
Mp 45–48 °C.
Mp 47–50 °C.
IR (KBr): 3343 (OH), 2959, 2865 (CH), 1597, 1570.1 (Ar), 1477,
1453, 1419, 1361, 1292, 1258, 1201, 1170, 1067, 1012, 942, 864,
849, 829 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.38 [s, 36 H, C(CH3)3], 4.65 (s, 2
H, ArCH2OH), 4.99 (s, 4 H, PyCH2OAr), 6.59 (t, 4J = 2.2 Hz, 1 H,
ArH), 6.67 (d, 4J = 2.2 Hz, 2 H, ArH), 7.15 (s, 4 H, PyH).
13C NMR (CDCl3, 75 MHz): d = 30.1 [q, C(CH3)3], 37.7 [s,
C(CH3)3], 65.2 (t, ArCH2OH), 69.5 (t, PyCH2OAr), 101.2 [d,
Ar(CH)], 105.8 [d, Ar(CH)], 113.7 [d, Py(CH)], 143.6 [s, Ar(C-1)],
145.2 [Py(C-4)], 160.0 [s, Ar(C-3,5)], 168.1 [s, Py(C-2,6)].
IR (KBr): 2958, 2859 (C-H), 1593, 1570 (Ar), 1479, 1447, 1420,
1358, 1202, 1166, 1070, 859 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.36 [s, 36 H, C(CH3)3], 4.43 (s, 2
4
H, ArCH2Br), 5.03 (s, 4 H, PyCH2OAr), 6.60 (t, J = 2.2 Hz, 1 H,
ArH), 6.68 (d, 4J = 2.2 Hz, 2 H, ArH), 7.13 (s, 4 H, PyH).
13C NMR (75 MHz, CDCl3): d = 30.1 [q, C(CH3)3], 33.4 (t,
ArCH2OH), 37.7 [s, C(CH3)3], 69.6 (t, PyCH2OAr), 102.2 [d,
Ar(CH)], 108.3 [d, Ar(CH)], 113.7 [d, Py(CH)], 139.9 [s, Ar(C-1)],
145.0 [s, Py(C-4)], 159.9 [s, Ar(C-3,5)], 168.1 [s, Py(C-2,6)].
MS (EI, 70 eV): m/z (%) = 610 (100) [M+], 608 (98) [M+], 595 (17),
593 (18), 529 (36), 486 (13), 203 (70), 189 (74), 174 (16), 148 (14).
MS (EI, 70 eV): m/z (%) = 546 (100) [M+], 531 (31), 504 (20), 203
(23), 189 (34), 147 (7), 71 (8).
Anal. Calcd for C35H49BrN2O2 (609.71): C, 68.95; H, 8.10; N, 4.59.
Found: C, 69.14; H, 8.05; N, 4.44.
Anal. Calcd for C35H50N2O3 (546.81): C, 76.88; H, 9.22; N, 5.12.
Found: C, 76.76; H, 9.10; N, 4.99.
3,5-Bis[3,5-bis(2,6-di-tert-butylpyridin-4-ylmethoxy)benzyl-
oxy]benzyl Bromide (13)
3,5-Bis[3,5-bis(2,6-di-tert-butylpyridin-4-ylmethoxy)benzyl-
oxy]benzyl Alcohol (12)
According to the general procedure, 7 (4.54 g, 7.46 mmol), 3,5-di-
hydroxybenzyl alcohol (5, 0.5 g, 3.3 mmol), anhyd K2CO3 (1.24 g,
9.00 mmol) and 18-C-6 (0.44 g, 1.66 mmol) were reacted for 7 d.
Chromatography (cyclohexane–Et2O, 4:1; Rf 0.15) gave 2.3 g
(58%) of 12 as a slightly yellow, glassy solid.
According to the general procedure, 12 (620 mg, 517 mmol), CBr4
(216 mg, 650 mmol) and PPh3 (171 mg, 650 mmol) were reacted. Af-
ter 30 min, additional CBr4 (108 mg, 325 mmol) and PPh3 (86 mg,
325 mol) were added because TLC showed unreacted starting ma-
terial. After a further 30 min, the mixture was worked up as de-
scribed. Chromatography (cyclohexane–Et2O, 4:1; Rf 0.6) gave 549
mg (84%) of 13 as a colorless, glassy solid.
Mp 45–49 °C.
Mp 48–52 °C.
IR (KBr): 3450 (OH), 2957, 2863, (CH), 1597, 1570 (Ar), 1456,
1418, 1360, 1255, 1203, 1163, 1054, 900, 857, 822 cm–1.
IR (KBr): 2956, 2862 (CH), 1597, 1571 (Ar), 1457, 1418, 1360,
1255, 1202, 1162, 1054, 900, 857, 821 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 [s, 72 H, C(CH3)3], 4.66 (s, 2
H, ArCH2OH), 4.98 (br s, 12 H, PyCH2OAr, ArCH2OAr), 6.57 [mc
(t), 4J = 2.2 Hz, 1 H, ArH], 6.60 (t, 4J = 2.2 Hz, 2 H, ArH), 6.66 [mc
(d), 4J = 2.2 Hz, 2 H, ArH], 6.71 (d, 4J = 2.2 Hz, 4 H, ArH), 7.15 (br
s, 8 H, PyH).
13C NMR (75 MHz, CDCl3): d = 30.1 [q, C(CH3)3], 37.7 [s,
C(CH3)3], 65.2 (t, ArCH2OH), 69.6, 70.1 (2 t, PyCH2OAr,
ArCH2OAr), 101.3, 101.5, 105.6, 106.5, 113.7 [several d, ArCH,
Py(C-3,5)], 139.4 [s, Ar(C-1)], 143.5 [s, Ar(C)CH2OH], 145.1 [s,
Py(C-4), 160.1 [s, Ar(C-3,5)], 168.1 [s, Py(C-2,6)].
1H NMR (300 MHz, CDCl3): d = 1.32 [s, 72 H, C(CH3)3], 4.42 (s, 2
H, ArCH2Br), 5.00 (br s, 12 H, PyCH2OAr, ArCH2OAr), 6.56 [mc
(t), 4J = 2.2 Hz, 1 H, ArH), 6.61 (t, 4J = 2.2 Hz, 2 H, ArH), 6.66 [mc
(d), 4J = 2.2 Hz, 2 H, ArH], 6.72 (d, 4J = 2.2 Hz, 4 H, ArH), 7.14 (br
s, 8 H, PyH).
13C NMR (75 MHz, CDCl3): d = 30.1 [q, C(CH3)3], 37.7 [s,
C(CH3)3], 65.2 (t, ArCH2Br), 69.6, 70.1 (2 × t, PyCH2OAr,
ArCH2OAr), 101.3, 101.5, 105.6, 106.5, 113.7 [several d, ArCH,
Py(C-3,5)], 139.4 [s, Ar(C-1)], 143.5 (s, ArCCH2Br), 145.1 [s,
Py(C-4)], 160.1 (s, Ar(C-3,5)], 168.1 [s, Py(C-2,6)].
MS (EI, 70 eV): m/z (%) = 1197 (43) [M+], 992 (18), 607 (12), 598
(11), 529 (38), 203 (100), 189 (39).
MS (EI, 70 eV): m/z (%) = 1260 (43%) [M+], 992 (18), 607 (12),
598 (11), 529 (38), 203 (100), 189 (39).
Anal. Calcd for C77H104N4O7 (1197.73): C, 77.21; H, 8.75; N, 4.68.
Found: C, 77.40; H, 8.72; N, 4.66.
Anal. Calcd. for C77H103BrN4O6 (1260.63): C, 73.36; H, 8.23; N,
4.44. Found: C, 73.31; H, 8.19; N, 4.50.
Dendrons 7 and 13; General Procedure
Dendritic benzyl alcohol 6 or 12 (1.0 equiv) was dissolved in as lit-
tle freshly distilled, anhyd THF as necessary to give a clear solution.
Under nitrogen, PPh3 (1.2–1.3 equiv) and CBr4 (1.2–1.3 equiv)
were added, and the mixture was stirred at r.t. The reaction was
stopped when TLC showed no more starting material or the mixture
turned yellow due to the formation of decomposition products; this
usually took 15–200 min. If starting material could still be detected
after 30 min by TLC, PPh3 (0.6 equiv) and CBr4 (0.6 equiv) were
Dendrimers 10 and 14; General Procedure
A mixture of dendritic benzylbromide 7 or 13 (2.2–2.3 equiv), 4,4¢-
dihydroxybiphenyl (8, 1 equiv), anhyd K2CO3 (3.0–3.3 equiv), and
18-C-6 (0.3–0.6 equiv) was dissolved in anhyd acetone (50 mL) and
heated to reflux under nitrogen for 3–8 d, until no further conversion
was observed by TLC. After cooling to r.t. and evaporation of the
solvent, the solid residue was dissolved in a threefold excess of H2O
(30 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with
Synthesis 2005, No. 9, 1383–1388 © Thieme Stuttgart · New York

PAPER
2,6-Di-tert-butylpyridine-Loaded Dendrimers
1387
CH2Cl2 (3–6 × 10–50 mL). The combined organic layer was dried
with MgSO4, and after evaporation of the solvent, the crude product
was purified by chromatography (300–500-fold excess of silica
gel).
in vacuo, the residue was dissolved in a threefold excess of H2O (30
mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with
CH2Cl2 (6 × 10–50 mL). The combined organic layer was dried with
MgSO4 and the solvent was evaporated in vacuo. The crude product
was purified by chromatography (500-fold excess of silica gel).
4,4¢-Bis[3,5-bis(2,6-di-tert-butylpyridin-4-ylmethoxy)benzyl-
oxy]biphenyl (10)
According to the general procedure, 7 (120 mg, 197 mmol), 4,4¢-di-
hydroxybiphenyl (8, 17 mg, 94 mmol), anhyd K2CO3 (32.0 mg, 235
mmol), and 18-C-6 (8.0 mg, 28 mmol) were reacted for 6 d. Chroma-
tography (cyclohexane–Et2O, 5:1; Rf 0.35) gave 100 mg (81%) of
10 as a colorless, glassy solid.
1,1,1-Tris{4-[3,5-bis(2,6-di-tert-butylpyridin-4-ylmethoxy)ben-
zyloxy]phenyl}ethane (11)
According to the general procedure, 7 (120 mg (197 mmol), 1,1,1-
tris(4-hydroxyphenyl)ethane (9, 18 mg, 60 mmol), anhyd K2CO3 (33
mg, 240 mmol), and 18-C-6 (5 mg, 20 mmol) were reacted for 6 d.
Chromatography (cyclohexane–Et2O, 4:1; Rf 0.75) gave 80 mg
(72%) of 11 colorless, glassy solid.
Mp 60–65 °C.
Mp 60–64 °C.
IR (KBr): 2958, 2860 (CH), 1597, 1570 (Ar), 1497, 1456, 1418,
1359, 1280, 1213, 1163, 1058, 901, 856, 825 cm–1.
IR (KBr): 2956, 2864 (C-H), 1597, 1570, 1507 (Ar), 1457, 1418,
1360, 1294, 1247, 1165, 1063, 1018, 942, 900, 858, 830 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.35 [s, 72 H, C(CH3)3], 5.01 (s, 8
H, PyCH2OAr), 5.06 (s, 4 H, ArCH2O–core), 6.61 (t, 4J = 2.2 Hz, 2
1H NMR (200 MHz, CDCl3): d = 1.35 [s, 108 H, C(CH3)3], 2.1 (s, 3
H, core–CCH3), 4.98 (s, 6 H, ArCH2O–core), 5.02 (s, 12 H,
PyCH2OAr), 6.60 (t, 4J = 2.2 Hz, 3 H, ArH), 6.72 (d, 4J = 2.2 Hz, 6
H, ArH), 6.87 (d, 3J = 8 Hz, 6 H, core-H), 6.87 (d, 3J = 8 Hz, 6 H,
core-H), 7.13 (s, 12 H, PyH).
13C NMR (75 MHz, CDCl3): d = 29.7 (q, core–CCH3), 30.1 [q,
C(CH3)3], 37.7 [s, C(CH3)3], 69.6 (t, ArCH2O–core), 69.9 (t,
PyCH2OAr), 101.5 [d, Ar(CH)], 106.4 [d, Ar(CH)], 113.8 [d, Py(C-
3,5)], 115.1 [d, core(CH)], 127.7 [d, core(CH)], 133.7 [s, core(C-
1)], 139.7 [s, Ar(C-1)], 145.1 [s, Py(C-4), 157.8 [s, core(C-4)],
160.1 [s, Ar(C-3,5)], 168.1 [Py(C-2,6)].
3
H, ArH), 6.74 (d, 4J = 2.2 Hz, 4 H, ArH), 7.01 (d, J = 8 Hz, 4 H,
core-H), 7.15 (s, 8 H, PyH), 7.42 (d, 3J = 8 Hz, 4 H, core-H).
13C NMR (75 MHz, CDCl3): d = 30.1 [q, C(CH3)3], 37.7 [s,
C(CH3)3], 69.6 (t, ArCH2O–core), 69.9 (t, PyCH2OAr), 102.2 [d,
Ar(CH)], 106.6 [d, core(CH)], 108.3 [d, Ar(CH)], 113.3 [d, Py(C-
3,5)], 129.7 [d, core(CH)], 139.9 [s, Ar(C-1)], 142.1 [s, core(C-
1,1¢), 145.0 [s, Py(C-4)], 156.8 [s, core(C-4,4¢), 159.9 [s, Ar(C-
3,5)], 168.1 [s, Py(C-2, 6)].
MS (EI, 70 eV): m/z (%) = 1243 (25) [M+], 714 (6), 529 (56), 325
(10), 203 (100).
MS (CI, isobutane): m/z (%) = 1893 (8) [M+ + 1], 1362 (9), 622 (5),
531 (22), 515 (17), 203 (100), 190 (32), 174 (11), 163 (20), 149
(18).
Anal. Calcd for C82H106N4O6 (1243.81): C, 79.18; H, 8.59; N, 4.50.
Found: C, 79.00; H, 8.40; N, 4.63.
4,4¢-Bis{3,5-bis[3,5-bis(2,6-di-tert-butylpyridin-4-ylmeth-
oxy)benzyloxy]benzyloxy}biphenyl (14)
Anal. Calcd for C125H162N6O9 (1892.76): C, 79.32; H, 8.63; N, 4.44.
Found: C, 79.18; H, 8.80; N, 4.31.
According to the general procedure, 13 (250 mg, 198 mmol), 4,4¢-
dihydroxybiphenyl (8, 17 mg, 94 mmol), anhyd K2CO3 (36 mg, 262
mmol) and 18-C-6 (10 mg, 38 mmol) were reacted for 6 d. Chroma-
tography (cyclohexane–Et2O, 4:1; Rf 0.8) gave 135 mg (63%) of 14
as a slightly yellow, glassy solid.
1,1,1-Tris(4-{3,5-bis[3,5-bis(2,6-di-tert-butyl-pyridin-4-yl-
methoxy)benzyloxy]benzyloxy}-phenyl)ethane (15)
According to the general procedure, 13 (110 mg, 120 mmol), 1,1,1-
tris(4-hydroxyphenyl)ethane (9, 11 mg, 36 mmol), anhyd K2CO3 (20
mg, 144 mmol), and 18-C-6 (8 mg, 15 mmol) were reacted for 8 d.
Chromatography (cyclohexane–Et2O, 4:1; Rf 0.8.) gave 86 mg
(58%) of 15 as a colorless glassy solid.
Mp 63–68 °C.
IR (KBr): 2961, 2922, 2860 (CH), 1597, 1570 (Ar), 1498, 1457,
1418, 1360, 1261, 1163, 1095, 1021, 900, 858, 802, 682 cm–1.
Mp 68–71 °C.
1H NMR (300 MHz, CDCl3): d = 1.34 [s, 144 H, C(CH3)3], 5.02 (br
s, 28 H, ArCH2O–core, ArCH2OAr, PyCH2OAr), 6.60 [mc (t) 4J =
2.2 Hz, 6 H, ArH], 6.73 [mc, (d), 4J = 2.2 Hz, 12 H, ArH), 7.00 (d,
3J = 8 Hz, 4 H, core-H), 7.15 (s, 16 H, PyH), 7.44 (d, 3J = 8 Hz, 4
H, core-H).
13C NMR (75 MHz, CDCl3): d = 30.1 [q, C(CH3)3], 37.8 [s,
C(CH3)3], 69.6, 69.7 (2 t, ArCH2OAr, ArCH2O–core, PyCH2OAr),
101.6, 106.6, 106.7, 113.8, 115.1, 127.7, 133.2 [several d, ArCH,
core-CH, Py(C-3,5)], 139.3 [s, Ar(C-1)], 141.3 [s, core(C-1,1¢),
145.1 [s, Py(C-4)], 157.1 [s, core(C-4,4¢)], 160.0 [s, Ar(C-3,5)],
168.1 [s, Py(C-2,6)].
IR (KBr): 2958, 2923, 2861 (CH), 1597, 1570, 1497 (Ar), 1458,
1419, 1360, 1257, 1203, 1161, 1049, 900, 856, 828, 770, 681 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.34 [s, 216 H, C(CH3)3], 2.06 (s,
3 H, core-CCH3), 4.99 (br s, 42 H, ArCH2O–core, ArCH2OAr,
4
PyCH2OAr), 6.60 [mc (t), J = 2.2 Hz, 9 H, ArH], 6.71 [mc (d),
4J = 2.2 Hz, 18 H, ArH), 6.86 (d, 3J = 8 Hz, 6 H, core-H), 7.00 (d,
3J = 8 Hz, 6 H, core-H), 7.14 (br s, 24 H, PyH).
13C NMR (75 MHz, CDCl3): d = 28.9 (q, core-CCH3), 29.9 [q,
C(CH3)3], 36.7 [s, C(CH3)3], 49.6 (s, core-CCH3), 66.2, 68.7, 69.5
(several t, ArCH2OAr, ArCH2O–core, PyCH2OAr), 100.5, 105.5,
106.6, 112.6, 113.0, 128.7 [several d, ArCH, core-CH, Py(C-3,5)],
138.5 [s, Ar(C-1)], 141.1 [s, core(C-1)], 144.1 [s, Py(C-4)], 155.8
[s, core(C-4)], 159.0 [s, Ar(C-3,5)], 167.0 [s, Py(C-2,6)].
MS (MALDI-TOF, THF, dithranol as matrix): m/z = 3845 [M+],
2992, 2868, 2721, 2396, 2015, 1850, 1747, 1612, 1196, 870, 656,
642, 614, 580, 545, 532, 505, 477, 463, 454, 438, 422, 408, 394.16
MS (MALDI-TOF, THF, dithranol as matrix): m/z = 2544 [M+],
2421, 2341, 2219, 2107, 2016, 1894, 1691, 1365, 1179, 1130, 1069,
1040, 870, 715, 642, 532, 505, 477, 450, 438, 422.15
Anal. Calcd for C166H214N8O14 (2543.63): C, 78.32; H, 8.47; N,
4.40. Found: C, 78.19; H, 8.50; N, 4.44.
Dendrimers 10 and 15; General Procedure
Anal. Calcd for C251H324N12O21 (3845.53): C, 78.40; H, 8.49; N,
4.37. Found: C, 78.45; H, 8.49; N, 4.33.
A mixture of the dendritic benzylbromide 7 or 13 (3.2–3.3 equiv),
1,1,1-tris(4-hydroxyphenyl)ethane (9, 1 equiv), anhyd K2CO3 (4.5–
5.0 equiv), and 18-C-6 (0.5–0.7 equiv) was dissolved in anhyd ace-
tone (70 mL). The mixture was heated to reflux for 5–8 d until no
further reaction was observed by TLC. The solvent was evaporated
Synthesis of Cyclohexenyl-1-triflate (4) from 2b
2,6-Di-tert-butyl-4-methylpyridine (2b, 4.1 g, 20 mmol) was dis-
solved in anhyd CH2Cl2 (15 mL); cyclohexanone (3, 1.8 g, 18
Synthesis 2005, No. 9, 1383–1388 © Thieme Stuttgart · New York

1388
U. Lüning, T. Marquardt
PAPER
Table 2 Batch Sizes for the Syntheses of Cyclohexen-1-yl Triflate
(4) from Cyclohexanone (3) with Tf2O
mmol) and Tf2O (5.4 mg, 19 mmol) were added. The mixture was
stirred at r.t. under argon for 24 h, towards the end of the reaction a
precipitate formed. The solvent was evaporated in vacuo and the
residue was dissolved in n-pentane (ca. 100 mL). The remaining
solid was filtered off and washed several times with n-pentane (3 ×
30 mL). The combined organic layer was washed with cold 1 N HCl
(ca. 50 mL) and brine (ca. 50 mL). After drying with anhyd K2CO3
the solvent was evaporated in vacuo and the residue was distilled
(70–72 °C/14 Torr, Lit.4,17 75–78 °C/15 Torr) yielding 3.0 g (70%,
Lit.4,5 76%) of 4 as a colorless liquid in 98.5% purity by GC [col-
umn: Optima 1.25 m; temperature program: 5 min at 50 °C, 5 °C/
min until 200 °C, 15 min at 200 °C, 20 °C/min until 250 °C, 20 min
at 250 °C; cyclohexanone (3): tR 4.6 min, cyclohexenyl-1-triflate 4:
tR 10.1 min, 2,6-di-tert-butyl-4-methylpyridine (2b): tR 17.7 min,
internal standard (n-hexadecane): tR 26.1 min].
DTBP
Amount
n-C16H34 Yield
Recovery
[mg (%)]
[mg (mmol)]
(mg)
17.9
42
[mg (%)]
2b
10
11
14
15
23 (110)
34 (27)
35 (18)
35 (14)
35 (9)
17.7 (77)
17.0 (74)
16.6 (72)
17.1 (74)
17.3 (75)
28.5 (85)
28.0 (80)
30.4 (87)
29.8 (85)
32
41
27
1H NMR (200 MHz, CDCl3): d = 1.56 (m, 2 H), 1.73 (m, 2 H), 2.13
(m, 2 H), 2.29 (m, 2 H), 5.71 (m, 1 H).
References
MS (EI, 70 eV): m/z = 230 (M+).
(1) Concave Reagents, 44: Konrad, S.; Näther, C.; Lüning, U.
Eur. J. Org. Chem. 2005, in press.
(2) Diederich, F.; Stang, P. J. Metal-Catalysed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998.
Synthesis of Cyclohexenyl-1-triflate (4) with a Range of DTBPs
All reactions were carried out in 5 mL vials sealed with teflon septa.
The reagents were added in the following sequence: 2b (1.1 equiv),
or the analogous dendrimers 10, 11, 14, or 15 [calculated on a
DTBP unit per of cyclohexanone (3), see Table 2)], cyclohexanone
(3, 10 mg, 100 mmol), anhyd CH2Cl2 (2 mL), and Tf2O (30 mg, 106
mmol). The vial was flushed with argon and sealed, a needle con-
nected to an argon balloon was pierced through the septum. The
mixtures were stirred for 6 h at r.t. Near the end of the reaction, pre-
cipitated solid was filtered off. The filtrate was evaporated in vacuo,
the residue was dissolved in n-pentane (ca. 20 mL), filtered through
basic Al2O3 which was washed with n-pentane (ca. 20 mL). After
evaporation of the solvent, a known amount of n-hexadecane was
added (Table 2). Then, the mixture was diluted with CH2Cl2 to give
a total volume of 50 mL. The yields were determined by GC as de-
scribed above.
(3) Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of
Palladium-Catalyzed Organic Reactions, Synthetic Aspects
and Catalytic Cycles; Academic Press: San Diego, 1997.
(4) Stang, P. J.; Treptow, W. Synthesis 1980, 283.
(5) Wright, M. E.; Pulley, S. R. J. Org. Chem. 1987, 52, 5036.
(6) Newkome, G. R.; Moorefield, C. N.; Vögtle, F. Dendritic
Molecules, Concepts, Syntheses, Perspectives; VCH:
Weinheim, 1996.
(7) Newkome, G. R.; Moorefield, C. N.; Vögtle, F. Dendrimers
and Dendrons, Concepts, Syntheses, Applications; Wiley-
VCH: Weinheim, 2001.
(8) (a) Topics in Current Chemistry Dendrimers I – V, Vol. 197;
Springer: Heidelberg, 1998. (b) Topics in Current
Chemistry Dendrimers I – V, Vol. 210; Springer:
Heidelberg, 2000. (c) Topics in Current Chemistry
Dendrimers I – V, Vol. 212; Springer: Heidelberg, 2001.
(d) Topics in Current Chemistry Dendrimers I – V, Vol. 217;
Springer: Heidelberg, 2001. (e) Topics in Current
Chemistry Dendrimers I – V, Vol. 228; Springer:
Heidelberg, 2003.
(9) Lüning, U. Liebigs Ann. Chem. 1987, 949.
(10) Lüning, U.; Baumstark, R.; Peters, K.; v. Schnering, H. G.
Liebigs Ann. Chem. 1990, 129.
(11) Marquardt, T.; Lüning, U. Chem. Commun. 1997, 1681.
(12) Lüning, U.; Marquardt, T. J. Prakt. Chem. 1999, 341, 222.
(13) Anderson, A. G.; Stang, P. J. J. Org. Chem. 1976, 41, 3034.
(14) As an intermediate, 2d has been described in the synthesis of
1,2-bis(2,6-di-tert-butylpyridinyl)ethane: Hou, C. J.;
Okamoto, Y. J. Org. Chem. 1982, 47, 1977.
Recycling of the Dendritic Bases 10, 11, 14, and 15
The residues of the reactions using the dendrimer-fixed DTBPs 10,
11, 14, and 15 were mixed with i-Pr2NH–benzene solution (1:4, 5
mL) and stirred for 10 min at r.t. The reaction was quenched with
H2O (10 mL). After filtration, the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL) and the combined organic layer was dried with
MgSO4. After evaporation of the solvent, the combined residues
were stirred with a THF–i-Pr2NH solution (9:1, 5 mL) for 10 min at
r.t. The reaction was quenched with H2O (10 mL) and filtered. The
aqueous layer was extracted with CH2Cl2 (3 × 30 mL), the com-
bined organic layer was dried with MgSO4, and the solvents were
evaporated in vacuo. Thus 70–80% of the dendrimers 10, 11, 14,
and 15 could be regenerated. Further material could be extracted
from Al2O3 thus increasing the yield to 80–90% (Table 2).18
(15) Besides M+ and M+ + 1, a signal at 2219 [M+ – 325] was
detectable but did not match any fragments. Relative
intensities did not change upon variation of the laser power.
Possibly, impure dendrons have been used lacking one
pyridine and one dihydroxybenzyl alcohol unit. In other
batches using dendrons which had been purified by GPC,
this impurity could be avoided.
All dendrimer-fixed DTBPs 10, 11, 14, and 15 remained active in
the triflate reaction over several reaction/recovery cycles, however,
a change of color from colorless to dark yellow slowly occurred.
This is in accordance with the observation that the dendrimer-fixed
DTBPs decomposed slowly when stored for months. In these cases,
the purity of the yellow compounds was checked by GPC and GPC
purification was carried out if necessary.
(16) As for 14, [M+ – 325] signals could be detected (m/z = 3519),
probably because the dendron contained the same impurity.
Again, the impurity could be avoided when dendron 13 was
purified by GPC.
For better recovery of the dendrimer-fixed DTBPs, the reaction
time was reduced to 5 h in order to avoid decomposition in the
strong acidic medium.
(17) Adah, S. A.; Nair, V. Tetrahedron 1997, 53, 6747.
(18) Sometimes the material had to be purified by GPC which
lowered the yield.
Synthesis 2005, No. 9, 1383–1388 © Thieme Stuttgart · New York