Synthesis of 2,2-functionalized benzo[1,3]dioxoles

Article abstract of DOI:10.1016/j.tet.2009.02.053

Highly functionalized catechol ketals exhibiting either a tert-butyl moiety or a spiro center in position 2 are synthesized by ketalization and functionalized in a sequence of subsequent transformations. By a specific ketalization protocol catechol ketals

Full text of DOI:10.1016/j.tet.2009.02.053

Tetrahedron 65 (2009) 3773–3779
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Tetrahedron
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Synthesis of 2,2-functionalized benzo[1,3]dioxoles
,
,
*
Nader M. Boshta a b, Martin Bomkamp a, Siegfried R. Waldvogel a
a Rheinische Friedrich-Wilhelms-Universita¨t Bonn, Kekule´-Institut fu¨r Organische Chemie und Biochemie, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
b Department of Chemistry, Faculty of Science, Menoufiya University, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 January 2009
Received in revised form 13 February 2009
Accepted 13 February 2009
Available online 27 February 2009
Highly functionalized catechol ketals exhibiting either a tert-butyl moiety or a spiro center in position 2
are synthesized by ketalization and functionalized in a sequence of subsequent transformations. By
a specific ketalization protocol catechol ketals of enolizable
b-keto esters can be prepared. With the
succeeding steps these compounds incorporate moieties, which are not compatible and accessible by
direct ketalization of catechol.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ketalization
Catechol
Benzo[1,3]dioxole
Functional group transformations
1. Introduction
ketone require specific reaction conditions in order to perform the
transformation successfully. We report the preparation of variety of
Benzo[1,3]dioxoles with tert-butyl substituent in position 2 play
an important role as planar,
-rich, and rigid building blocks.1
differently substituted benzo[1,3]dioxoles in the ketal moiety.
p
Furthermore, for the determination of attached stereo centers us-
ing enantiomerically pure 2-tert-butyl-2-methylbenzo[1,3]dioxole
carboxylic acid has found significant attention.2 These architectures
can also be exploited for fluorescent sensors.3 More recently,
functionalized catechol ketals have found application in the syn-
thesis of triphenylene ketals by oxidative trimerization.4 By this
synthetic pathway using MoCl5 or anodic protocols, the first arti-
ficial caffeine receptors were established.5 Such unique platforms
starting from catechol ketals gave rise to a variety of novel effects6
and sensor applications.7 The rigid nature of the ketal unit in the
2,2-disubstituted benzo[1,3]dioxole is crucial for a powerful ap-
plication later on.8 Spiro ketals or ketals exhibiting a tert-butyl
moiety lead to a well defined arrangement of functional groups. The
installation of substituents in position 2 of the benzo[1,3]dioxole
can be achieved by electrophilic displacement of a chloro moiety by
ketene acetals.9 The more common synthetic pathway exploits the
condensation with catechol under acidic conditions using sulfonic
acids or their metal salts.10 For good conversions either the formed
water is continuously removed or dehydrating agents are applied.11
Since those reaction conditions are harsh the synthesis of appro-
priately functionalized catechol ketals remains still a significant
issue.12 In particular, tert-butyl groups adjacent to carbonyl of the
2. Results and discussion
The synthesis of catechol ketals commenced with the trans-
formation of a
ence of maximum 0.1 equiv of p-toluenesulfonic acid in toluene
(Scheme 1) using a Dean–Stark trap. Some of these -keto esters
were commercially available and others have been prepared by
b-keto ester with 1.5 equiv of catechol in the pres-
b
alkylation of the corresponding
b
-keto esters.
OR4
R3
O
O
O
OH
OH
R2
PTSA
R1
OR4
O
O
R2 R3
toluene
reflux
R1
Scheme 1.
The yields of the obtained catechol ketals were strongly de-
pendent on the nature of the -keto ester. Especially when steric
b
hindrance is involved catechol ketals do not form easily. Therefore,
thermal activation is required. Shifting of the ketalization equilib-
rium by removal of water is for acceptable yields necessary. Eno-
lizable ketones (Table 1, entries 1, 2, 8, and 9) are under these
conditions prone to decarboxylation and lead carbonyl components
with lost functionality for later application and more important,
they exhibit a less sterically demanding environment. Conse-
quently, a significant byproduct is the benzodioxole derived from
* Corresponding author. Tel.: þ49 228 732653; fax: þ49 228 739608.
E-mail address: waldvogel@uni-bonn.de (S.R. Waldvogel).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.053

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N.M. Boshta et al. / Tetrahedron 65 (2009) 3773–3779
Table 1
boiling reaction mixture. Continuous removal of water was per-
Ketalization of enolizable and non-enolizable
b
-keto esters
Ketal
OMe
formed by a Dean–Stark apparatus. This protocol gave access to 23–
38% isolated yield. Application of other ketalization methods in-
volving dehydrating agents gave inferior yields. Non-enolizable
substrates rendered significantly higher yields (entries 3–5, 10, 11).
All catechol ketals form colorless oils that are purified by distilla-
tion or by chromatography on silica.
In particular compound 8 is of specific interest for receptor
applications.8 Consequently, more attention was given to the con-
version of this intermediate. Treatment of catechol ketal 8 with
lithium aluminum hydride in ether under reflux conditions for 3 h
gave rise to the corresponding alcohol 12 in 77% yield.13 Sub-
sequently, 12 was allowed to react with acetic anhydride or iso-
butyric acid anhydride in the presence of pyridine as a solvent to
afford 13 and 14, respectively (Scheme 2).
Entry
Starting material
Yield
29%
O
O
O
O
O
O
O
1
OMe
OEt
1
OEt
O
O
O
2
23%
2
OMe
O
O
O
3
4
70%
65%
R
O
OMe
O
O
O
3
O
OH
OEt
O
O
O
LiAlH4, diethylether
reflux, 2 h, 77%
R
2 O
O
O
O
O
O
O
8
OEt
pyridine
4
12
13 : R = CH3 86%
14 : R = CH(CH3)2 81%
O
O
O
OMe
MeO
OMe
O
Scheme 2.
5
6
64%
46%
O
O
The preparation of tosylate derivative 15 by treatment of 12 with
5
p-toluenesulfonyl chloride and pyridine,14 appeared to be a practi-
cal starting point for the elaboration into compounds 16, 17, 18, and
19 (Scheme 3). The introduction of an additional carbon atom was
achieved by nucleophilic substitution using cyanide anions pro-
viding 16 in very good yield.14 The versatile tosylate derivative 15
opens up by nucleophilic displacement a variety of functionalized
benzodioxoles as, e.g., the geminal dicyano derivative 17 by nu-
cleophilic substitution using malonitrile under basic conditions. For
an efficient installation of a nitro moiety a prior exchange to the
better leaving group iodide had to be made under typical Finkel-
stein conditions.15 The tosylate derivative 15 was converted to the
nitro compound 19 in two steps.16 Thus, iodination of 15 by sodium
iodide in acetone is followed by nitration using sodium nitrite in
DMF. The resulting nitro compound 19 was obtained in good yield
(Scheme 3).
O
O
OMe
O
O
O
6
O
O
O
7
38%
O
O
O
7
OEt
O
O
O
8
38%
35%
70%
72%
O
O
OEt
OEt
8
CN
OEt
O
O
O
9
O
O
b
O
O
9
16
NC
OEt
O
O
O
CN
OTs
O
10
11
OEt
OEt
O
O
a
O
O
O
O
c
12
10
OEt
17
O
15
O
R
O
O
11
O
O
d
the decarboxylated intermediate. When all reagents are added at
once (e.g., for 8) and the mixture is subsequently heated to reflux,
only traces of catechol ketals are detected. Cyclodehydration of 1,4-
dicarbonyl compounds is another side reaction that competes with
the ketalization process (Table 1, entry 5). To maximize the yield of
18 : R = I
e
19 : R = NO2
Scheme 3. Reagents and conditions: (a) TsCl, pyridine, overnight, rt, 80%; (b) NaCN,
DMSO, 80 ꢀC, 3 h, 84%; (c) malononitrile, K2CO3, DMF, 80 ꢀC, 4 h, 42%; (d) NaI, acetone,
reflux, 24 h, 81%; (e) NaNO2, DMF, rt, 5 h, 48%.
the desired highly functionalized catechol ketals, the
b-keto ester
was added drop by drop over a period of 8–12 h to the vigorously

N.M. Boshta et al. / Tetrahedron 65 (2009) 3773–3779
3775
Catechol ketal 8 was converted into nitrile 22 in three steps:
hydrolysis of the ester 8 with LiOH in THF/H2O to the acid 20,17
conversion of the acid to the carboxamide 21, and dehydration of
this carboxamide to give nitrile 22 in 88% yield. The dehydration
step was carried out with p-toluenesulfonyl chloride in pyridine.18
Other reaction conditions for dehydration of carboxamide in-
cluding Martin’s sulfurane,19 failed completely since either no re-
action was observed or the benzo moiety was attacked by
electrophilic side reactions (Scheme 4).
afforded 23, 25, and 26, respectively. Whereas DCC coupling of 20
with ethylene glycol monomethylether or diethylamine afforded 24
and 28, respectively. And finally, the treatment of catechol ketal 8
with morpholine at reflux conditions for 48 h gave 27 in satisfac-
tory yield (Table 2).
R
O
conditions
O
8 or 20
O
R
23-28
O
NC
a
Scheme 5.
c
O
O
O
O
8
3. Conclusion
20 : R = OH
21 : R = NH2
Benzo[1,3]dioxoles with substituents in position 2 are well ac-
cessible by ketalization of the carbonyl precursor using catechol.
When bulky moieties like tert-butyl groups are installed in position
22
b
Scheme 4. Reagents and conditions: (a) LiOH, THF, H2O, 4 days, rt, 95%; (b) NH4OH,
DCC, DMAP, CH2Cl2, rt, overnight, 68%; (c) TsCl, pyridine, rt, overnight, 88%.
2 of the heterocycle, decarboxylative degradation of the
b-keto
ester is a severe side reaction. Slow addition of the reaction partner
circumvents this particular challenge. For the introduction of other
functional groups subsequent conversions have to be applied. The
carboxylate 8 turned out to be a readily available and versatile
intermediate for a variety of 2,2-functionalized catechol ketals.
Subsequent transformations allow the installation of nitro, cyano,
iodo, chloro, amido, and many other moieties at the side chain,
which are not compatible with direct ketalization. These building
blocks represent not only valuable key precursors for receptors
based on triphenylene ketals but also might have their place in
other areas of molecular sciences.
Furthermore, the carboxylic acid 20 is a key intermediate, which
gave rise to a variety of compounds by alkylation or DCC coupling.
Alternatively, direct displacement of the ester 8 can be exploited as
well. The obtained compounds 23–28 are not accessible by direct
ketalization with catechol. Thus, alkylation of catechol ketal 20
with n-butyliodide, methyl bromoacetate, or 1,2-dichloroethane
Table 2
Results of Scheme 5
Nr.
Starting material
Product
OButyl
Yield
86%a
O
1
20
O
O
4. Experimental
4.1. General
23
OMe
O
All reagents were used in analytical grade. Solvents were des-
iccated if necessary by standard methods. Column chromatography
was performed on silica gel (particle size 63–200 mm, Merck,
Darmstadt, Germany) using mixtures of cyclohexane with ethyl-
acetate as eluents. Melting points were determined on a Melting
Point Apparatus SMP3 (Stuart Scientific, Watford Herts, UK) and
were uncorrected. Micro analyses were performed using a Vario EL
III (Elementar-Analysensysteme, Hanau, Germany). 1H NMR spectra
were recorded at 25 ꢀC on a Bruker DPX 300 or DPX 400 (Analy-
O
2
20
84%b
O
O
24
O
O
OMe
Cl
89%a
59%a
O
3
4
20
20
O
O
25
O
tische Messtechnik, Karlsruhe, Germany). Chemical shifts (d) are
O
reported in parts per million (ppm) relative to TMS as internal
standard or traces of CHCl3 in the deuterated solvent. Mass spectra
were obtained on a MAT8200, MAT95XL (Finnigan, Bremen, Ger-
many), MS50 (Kratos, Manchester, England) or FT-ICR (Bruker APEX
IV) employing EI, ESI, and HRMS.
O
O
26
O
N
N
70%c
O
5
8
4.1.1. General procedure for ketalization of enolizable b-keto esters
O
O
In a 500 mL two-necked flask, catechol (1.5 equiv) was dissolved
in 250 mL toluene. After addition of p-toluenesulfonic acid mono-
hydrate (0.1 equiv) the mixture was heated to vigorous reflux at
27
a Dean–Stark apparatus for about 2 h. Then, a solution of the b-keto
ester in dry toluene (100 mL) was added in 10 mL portions slowly
over a period of 10 h by using dropping funnel. The mixture was
heated under reflux overnight; H2O was collected by a Dean–Stark
trap. After concentration, the resulting oil was fractionated with
t-BuOMe (400 mL) and 3% NaOH soln (200 mL). The organic layer
was washed with H2O (5ꢁ200 mL) and brine (200 mL), dried
(anhyd MgSO4), and concentrated under reduced pressure. Upon
distillation of the crude product, the ketal product was obtained.
55%b
O
6
8
O
O
28
a
b
c
via alkylation with NaH and suitable alkylation means in DMF.
Conversion with DCC, DMAP, and suitable amine or alcohol.
Conversion of ketal 8 in boiling morpholine.

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N.M. Boshta et al. / Tetrahedron 65 (2009) 3773–3779
4.1.2. General procedure for ketalization of non-enolizable
as a colorless oil. 1H NMR (400 MHz, CDCl3):
6H), 1.17–1.43 (m, 8H), 1.64 (s, 3H), 1.76–1.88 (m, 4H), 3.63 (s, 3H),
6.73–6.78 (m, 4H); 13C NMR (100 MHz, CDCl3):
23.52, 26.82, 30.84, 51.77, 57.70, 108.21, 120.41, 120.98, 147.22,
173.57; MS (EI): m/z (%)¼320.2 (5) [M]ꢃþ; HRMS: m/z calcd for
C19H28NaO4 [MþNaþ] 343.1880, found 343.1871.
d
¼0.89 (t, J¼7.1 Hz,
b-keto ester
In a 500 mL two-necked flask, the
b-keto ester was dissolved in
d
¼13.94, 22.26,
toluene (250 mL). After addition of catechol (1.5 equiv) and p-tol-
uenesulfonic acid monohydrate (0.1 equiv), the mixture was heated
under reflux overnight; H2O was collected by a Dean–Stark trap.
After concentration, the resulting oil was fractionated with t-
BuOMe (400 mL) and 3% NaOH soln (200 mL). The organic layer
was washed several times with H2O (5ꢁ200 mL) and brine
(200 mL), dried (anhyd MgSO4), and concentrated under reduced
pressure. Upon distillation of the crude product, the ketal product
was obtained.
4.7. 2-(1,1-Dimethylethyl)-2-(2-methoxycarbonylethyl)-
benzo[1,3]dioxole (6)
Upon distillation of the crude product (195 ꢀC, 10ꢂ5 mbar), the
ketal (0.69 g, 46%) was obtained as a colorless oil. 1H NMR
(400 MHz, CDCl3):
d
¼1.04 (s, 9H), 2.43–2.37 (m, 4H), 3.62 (s, 3H),
6.70–6.75 (m, 4H); 13C NMR (100 MHz, CDCl3):
d
¼24.37, 27.27,
4.2. 2-Cyclohexyl-2(methoxycarbonylmethyl)benzo[1,3]-
dioxole (1)
29.35, 40.37, 51.61, 107.12, 120.84, 122.88, 148.81, 173.79; MS (EI,
70 eV): m/z (%)¼264.1 (18) [M]ꢃþ; HRMS: m/z calcd for C15H20O4
[M]þ 264.1362, found 264.1363.
Upon distillation of the crude product (101 ꢀC, 5.4ꢁ10ꢂ2 mbar),
the ketal product (1.5 g, 29%) was obtained as a colorless oil. 1H
NMR (300 MHz, CDCl3):
2.04–2.14 (m, 1H), 2.94 (s, 2H), 3.60 (s, 3H), 6.73–6.79 (m, 4H); 13C
NMR (75 MHz, CDCl3):
108.03, 118.59, 121.12, 147.53, 168.85; MS (EI): m/z (%)¼276.2 (80)
[M]ꢃþ. Anal. Calcd for C16H20O4: C, 69.54; H, 7.30. Found: C, 69.93; H,
7.44.
d
¼1.06–1.33 (m, 5H), 1.63–1.91 (m, 5H),
4.8. 2-(Acetoxymethyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (7)
d
¼25.80, 25.93, 25.97, 40.26, 45.06, 51.82,
Upon distillation of the crude product (117 ꢀC, 10ꢂ5 mbar), the
ketal (1.70 g, 38%) was obtained as a colorless oil. 1H NMR
(400 MHz, CDCl3):
d
¼1.09 (s, 9H), 1.82 (s, 3H), 4.48 (s, 2H), 6.75 (s,
4H); 13C NMR (100 MHz, CDCl3):
d
¼20.43, 24.39, 38.68, 63.59,
4.3. 2-(1-Adamantyl)-2-(ethoxycarbonylmethyl)-
benzo[1,3]dioxole (2)
107.24, 119.88, 120.86, 148.62, 170.54; MS (EI, 70 eV): m/z (%)¼250.1
(26) [M]ꢃþ; HRMS: m/z calcd for C14H18O4 [M]þ 250.1205, found
250.1207.
The crude product was chromatographed using cyclohexane–
ethylacetate (9:1) as eluent and the ketal product (1.8 g, 23%) was
obtained as a colorless solid. Mp 76–77 ꢀC; 1H NMR (400 MHz,
4.9. 2-(1,1-Dimethylethyl)-2-(ethoxycarbonylmethyl)-
benzo[1,3]dioxole (8)
CDCl3):
d
¼0.89 (t, J¼7.2 Hz, 3H), 1.63–1.74 (m, 12H), 1.99–2.04 (m,
3H), 2.94 (s, 2H), 3.88 (q, J¼7.2 Hz, 2H), 6.70–6.75 (m, 4H); 13C NMR
Upon distillation of the crude product (101 ꢀC, 1.3ꢁ10ꢂ2 mbar),
(100 MHz, CDCl3):
d¼13.55, 27.85, 35.26, 36.65, 38.60, 42.29, 60.75,
the ketal (26 g, 38%) was obtained as a colorless oil. 1H NMR
107.22, 120.09, 120.80, 148.62, 168.98; MS (EI): m/z (%)¼342.2 (35)
[M]ꢃþ. Anal. Calcd for C21H26O4: C, 73.66; H, 7.65. Found: C, 73.81; H,
7.73.
(400 MHz, CDCl3):
d
¼0.89 (t, J¼7.20 Hz, 3H), 1.07 (s, 9H), 2.96 (s,
2H), 3.88 (q, J¼7.20 Hz, 2H), 6.73 (s, 4H); 13C NMR (100 MHz,
CDCl3):
d
¼13.53, 24.15, 39.72, 40.71, 60.76, 107.33, 120.88, 148.61,
168.75; MS (ESþ): m/z¼287.1 [MþNa]þ; HRMS: m/z calcd for
4.4. 2-(2,2-Dimethyl acetic acid methylester)-2-methyl-
benzo[1,3]dioxole (3)
C15H20NaO4 [MꢂNaþ] 287.1254, found 287.1250.
4.10. Ethyl-spiro(benzo[1,3]dioxole-2,10-cycloheptane)-20-
carboxylate (9)
Upon distillation of the crude product (74 ꢀC, 2.7ꢁ10ꢂ2 mbar),
the ketal product (12.6 g, 70%) was obtained as a colorless oil. 1H
NMR (400 MHz, CDCl3):
d
¼1.35 (s, 6H), 1.68 (s, 3H), 3.68 (s, 3H),
Upon distillation of the crude product (127 ꢀC, 2.3ꢁ10ꢂ2 mbar),
6.77 (s, 4H); 13C NMR (100 MHz, CDCl3):
d
¼20.55, 21.30, 51.03,
the ketal (9.6 g, 35%) was obtained as a colorless oil. 1H NMR
52.12, 108.15, 119.73, 121.06, 147.44, 174.38; MS (ESþ): m/z¼259.1
[MþNaþ]. Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C,
65.94; H, 6.91.
(400 MHz, CDCl3):
d
¼0.86 (t, J¼7.10 Hz, 3H), 1.42–1.71 (m, 5H),
1.78–1.98 (m, 3H), 2.04–2.20 (m, 2H), 3.06 (dd, J¼3.30 Hz, 1H), 3.88
(q, J¼9.30 Hz, 2H), 6.64–6.70 (m, 4H); 13C NMR (75 MHz, CDCl3):
d
¼13.60, 21.22, 25.35, 26.75, 28.00, 38.27, 54.00, 60.56, 108.17,
4.5. 2-(1-Ethoxycarbonyl-1-(methyl)-ethyl)-2-propyl-
benzo[1,3]dioxole (4)
108.26, 120.00, 120.97, 121.01, 146.92, 147.43, 171.57; MS (EI): m/z
(%)¼276.1 (44) [M]ꢃþ. Anal. Calcd for C16H20O4: C, 69.54; H, 7.30.
Found: C, 69.64; H, 7.32.
Upon distillation of the crude product (98 ꢀC, 10ꢂ2 mbar), the
ketal (17.7 g, 65%) was obtained as a colorless oil. 1H NMR
(400 MHz, CDCl3):
1.32 (s, 6H), 1.34–1.44 (m, 2H), 2.00–2.04 (m, 2H), 4.09 (q, J¼7.10 Hz,
2H), 6.70–6.75 (m, 4H); 13C NMR (100 MHz, CDCl3):
d
¼0.88 (t, J¼7.40 Hz, 3H), 1.18 (t, J¼7.10 Hz, 3H),
4.11. Ethyl-20-methyl-spiro(benzo[1,3]dioxole-2,10-
cycloheptane)-20-carboxylate (10)
d
¼13.91, 14.00,
15.10, 20.58, 37.16, 51.69, 60.89, 107.17, 120.79, 120.85, 148.78,
174.01; MS (ESþ): m/z¼301.2 [MþNa]þ; HRMS: m/z calcd for
C16H22NaO4 [MþNa]þ 301.1410, found 301.1403.
Upon distillation of the crude product (132 ꢀC, 2.1ꢁ10ꢂ2 mbar),
the ketal (4.3 g, 70%) was obtained as a colorless oil. 1H NMR
(400 MHz, CDCl3):
7H), 2.07–2.17 (m, 2H), 2.40–2.46 (m, 1H), 4.09 (q, J¼7.1 Hz, 2H),
6.75 (s, 4H); 13C NMR (100 MHz, CDCl3):
d¼1.11 (t, J¼7.1 Hz, 3H),1.33 (s, 3H),1.57–1.82 (m,
4.6. 2-(1-Butyl)-1-(methoxycarbonyl)pentyl-2-methyl-
benzo[1,3]dioxole (5)
d¼13.84, 20.52, 20.85,
23.05, 26.78, 33.85, 35.87, 54.81, 60.60, 107.99, 108.27, 120.85,
120.86, 121.29, 147.22, 147.71, 174.02; MS (EI): m/z (%)¼290.1 (20)
[M]ꢃþ. Anal. Calcd for C17H22O4: C, 70.32; H, 7.64. Found: C, 70.27; H,
7.63.
The crude product was chromatographed using cyclohexane–
ethylacetate (9:1) as eluent, and the ketal (3.1 g, 64%) was obtained

N.M. Boshta et al. / Tetrahedron 65 (2009) 3773–3779
3777
4.12. Ethyl-20-methyl-spiro(benzo[1,3]dioxole-2,10-
cyclohexane)-20-carboxylate (11)
mixture was stirred overnight at rt. Then poured onto ice water. The
formed solid was filtered off, washed with pure water (3ꢁ50 mL) to
give tosylate 15 (0.14 g, 80%) as a colorless powder. Mp 46–47 ꢀC; 1H
Upon distillation of the crude product (131 ꢀC, 3.2ꢁ10ꢂ2 mbar),
NMR (400 MHz, CDCl3):
d
¼0.97 (s, 9H), 2.35 (t, J¼7.3 Hz, 2H), 2.41
the ketal (6.4 g, 72%) was obtained as a colorless oil. 1H NMR
(s, 3H), 4.11 (t, J¼7.3 Hz, 2H), 6.62–6.64 (m, 2H), 6.71–6.73 (m, 2H),
(400 MHz, CDCl3):
d
¼1.08 (t, J¼7.1 Hz, 3H), 1.33 (s, 3H), 1.45–1.61 (m,
7.24 (d, J¼8.0 Hz, 2H), 7.61 (d, J¼8.2 Hz, 2H); 13C NMR (100 MHz,
2H), 1.67–1.81 (m, 3H), 1.93–1.99 (m, 1H), 2.13 (ddd, J¼13.6, 7.3,
4.0 Hz, 1H), 2.23 (ddd, J¼13.8, 7.0, 3.9 Hz, 1H), 4.05 (q, J¼7.1 Hz, 2H),
CDCl3):
d
¼21.59, 24.09, 33.42, 40.37, 65.44, 107.44, 121.07, 121.62,
127.78, 129.72, 132.84, 144.59, 148.12; MS (EI, 70 eV): m/z (%)¼376.1
(14) [M]ꢃþ. Anal. Calcd for C20H24O5S: C, 63.81; H, 6.43; S, 8.52.
Found: C, 63.84; H, 6.52; S, 8.79.
6.73–6.77 (m, 4H); 13C NMR (100 MHz, CDCl3):
d¼13.84, 18.37, 21.26,
22.64, 32.47, 34.04, 51.09, 60.59,107.94,108.31,119.04, 120.81, 120.91,
147.41, 147.43, 173.72; MS (EI): m/z (%)¼276.1 (44) [M]ꢃþ; HRMS: m/z
calcd for C16H20NaO4 [MþNa]þ 299.1254, found 299.1251.
4.17. 2-(1,1-Dimethylethyl)-2-(2-cyanoethyl)-
benzo[1,3]dioxole (16)
4.13. 2-(1,1-Dimethylethyl)-2-(2-hydroxyethyl)-
benzo[1,3]dioxole (12)
A mixture of tosylate 15 (0.1 g, 0.27 mmol) and sodium cyanide
(0.02 g, 0.4 mmol) in dimethylsulfoxide (5 mL) was stirred at 80 ꢀC
for 2 h. Then poured onto ice water. The formed solid was filtered
off, washed with pure water (3ꢁ50 mL) to give 16 (0.051 g, 84%) as
a colorless powder. Mp 44–45 ꢀC; 1H NMR (400 MHz, CDCl3):
To an ice cooled solution of 8 (0.264 g, 1 mmol) in diethyl ether
(20 mL) was added LiAlH4 (0.16 g, 4 mmol). The reaction mixture
was stirred for 3 h at reflux and then carefully poured onto ice
water. The organic phase was separated and the aqueous phase was
extracted with t-BuOMe (100 mL). The organic layer was washed
several times with H2O (5ꢁ50 mL) and brine (50 mL), dried (anhyd
MgSO4), filtered, and evaporated to give 12 (0.17 g, 77%) as a color-
d
¼1.04 (s, 9H), 2.35–2.37 (m, 2H), 2.38–2.40 (m, 2H), 6.73–6.78 (m,
4H); 13C NMR (100 MHz, CDCl3):
d
¼10.92, 24.24, 30.32, 40.33,
107.48, 119.36, 121.32, 121.62, 148.34; MS (EI, 70 eV): m/z (%)¼231.1
(16) [M]ꢃþ. Anal. Calcd for C14H17O2N: C, 72.70; H, 7.41; N, 6.06.
Found: C, 72.21; H, 7.37; N, 5.97.
less powder. Mp 66–67 ꢀC; 1H NMR (400 MHz, CDCl3):
9H),1.81 (s,1H), 2.27 (t, J¼6.12 Hz, 2H), 3.75 (t, J¼6.12 Hz, 2H), 6.73–
6.77 (m, 4H); 13C NMR (100 MHz, CDCl3):
d
¼1.04 (s,
d¼24.23, 36.45, 40.44,
4.18. 2-(3,3-Dicyanopropyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (17)
57.82, 107.34, 121.05, 123.77, 148.51; MS (EI, 70 eV): m/z (%)¼222.1
(19) [M]ꢃþ. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C,
70.25; H, 8.26.
A mixture of malononitrile (1.75 g, 27 mmol) and K2CO3 (3.7 g,
27 mmol) in DMF (30 mL) was stirred for about 30 min at rt. Then,
tosylate 15 (2 g, 6 mmol) was added. The reaction mixture was
stirred for 3 h at 80 ꢀC, poured onto ice water and was extracted
with ethylacetate (200 mL). The organic layer was washed with
H2O (3ꢁ100 mL) and brine (100 mL), dried (anhyd MgSO4), and
filtered. Removal of the solvent afforded a residue, which was
chromatographed using cyclohexane–ethylacetate (9.5:0.5) as el-
uent to give 17 (0.60 g, 42%) as a colorless powder. Mp 56–57 ꢀC; 1H
4.14. 2-(2-Acetoxyethyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (13)
To a solution of 12 (0.11 g, 0.5 mmol) in pyridine (5 mL), 1 mL of
acetic acid anhydride was added. The reaction mixture was stirred
overnight at rt, poured onto ice water and extracted with t-BuOMe
(100 mL). The organic layer was washed several times with H2O
(5ꢁ50 mL) and brine (50 mL), dried (anhyd MgSO4), filtered, and
evaporated to give 13 (0.11 g, 86%) as a colorless powder. Mp 36–
NMR (400 MHz, CDCl3):
d
¼1.05 (s, 9H), 2.10–2.16 (m, 2H), 2.25–2.29
(m, 2H), 3.77 (t, J¼6.9 Hz, 1H), 6.73–6.80 (m, 4H); 13C NMR
37 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼1.04 (s, 9H),1.90 (s, 3H), 2.32 (t,
(100 MHz, CDCl3):
d¼22.50, 24.24, 24.38, 30.63, 40.49, 107.49,
J¼7.1 Hz, 2H), 4.17 (t, J¼7.1 Hz, 2H), 6.70–6.75 (m, 4H); 13C NMR
112.27, 121.45, 122.29, 148.25; MS (EI, 70 eV): m/z (%)¼270.1 (12)
[M]ꢃþ; HRMS: m/z calcd for C16H18N2O2 [M]þ 270.1368, found
270.1363.
(100 MHz, CDCl3):
d
¼24.24, 32.82, 40.48, 59.61, 107.34, 121.93,
122.18, 148.52, 170.88; MS (EI, 70 eV): m/z (%)¼264.1 (13) [M]ꢃþ
.
Anal. Calcd for C15H20O4: C, 68.76; H, 7.63. Found: C, 68.54; H, 7.737.
4.19. 2-(1,1-Dimethylethyl)-2-(2-iodoethyl)benzo[1,3]-
dioxole (18)
4.15. 2-(1,1-Dimethylethyl)-2-(2-isobutyryloxyethyl)-
benzo[1,3]dioxole (14)
A mixture of the tosylate 15 (0.377 g, 1 mmol) and sodium io-
dide (0.6 g, 4 mmol) in acetone (20 mL) was refluxed under inert
atmosphere for about 20 h. Then, the solvent was removed under
reduced pressure. Water was added to the residue, which was
extracted with ethylacetate (100 mL). The combined extracts were
washed with H2O (3ꢁ50 mL) and brine (50 mL), dried (anhyd
MgSO4), filtered, and evaporated to give iodide 18 (0.27 g, 81%) as
To a solution of 12 (0.55 g, 2.5 mmol) in pyridine (20 mL), 3 mL
of isobutyric acid anhydride was added. The reaction mixture was
stirred overnight at rt, poured onto ice water and extracted with t-
BuOMe (150 mL). The organic layer was washed with H2O
(5ꢁ50 mL) and brine (50 mL), dried (anhyd MgSO4), filtered, and
evaporated to furnish 14 (0.58 g, 81%) as a colorless oil. 1H NMR
(400 MHz, CDCl3):
J¼7.0 Hz, 2H), 2.37–2.42 (m, 1H), 4.17 (t, J¼7.0 Hz, 2H), 6.70–6.74
(m, 4H); 13C NMR (100 MHz, CDCl3):
d
¼1.04 (s, 9H), 1.09 (d, J¼7.0 Hz, 6H), 2.31 (t,
yellow needles. Mp 67–68 ꢀC; 1H NMR (400 MHz, CDCl3):
9H), 2.55–2.61 (m, 2H), 3.08–3.13 (m, 2H), 6.70–6.77 (m, 4H); 13C
d¼1.04 (s,
d¼24.21, 30.89, 32.88, 33.84,
NMR (100 MHz, CDCl3):
d
¼ꢂ4.50, 24.23, 39.84, 39.94, 107.24,
40.43, 59.36, 107.29, 120.86, 122.20, 148.48, 176.95; MS (EI, 70 eV):
m/z (%)¼292.1 (10) [M]ꢃþ; HRMS: m/z calcd for C17H24O4 [M]þ
292.1675, found 292.1675.
120.94, 123.19, 148.52; MS (EI, 70 eV): m/z (%)¼332.0 (18) [M]ꢃþ
.
Anal. Calcd for C13H17IO2: C, 47.00; H, 5.16. Found: C, 46.95; H, 5.26.
4.20. 2-(1,1-Dimethylethyl)-2-(2-nitroethyl)-
benzo[1,3]dioxole (19)
4.16. 2-(1,1-Dimethylethyl)-2-(2-(4-methylphenyl-
sulfonyloxy)-ethyl)benzo[1,3]dioxole (15)
A mixture of the iodide 18 (2 g, 6 mmol) and sodium nitrite
(1.25 g, 18 mmol) in DMF (20 mL) was kept at ambient conditions
for 5 h. The mixture was poured onto ice water. It was extracted
A solution of 12 (0.11 g, 0.5 mmol) in pyridine (5 mL) was treated
with 4-toluenesulfonyl chloride (0.15 g, 0.75 mmol). The reaction

3778
N.M. Boshta et al. / Tetrahedron 65 (2009) 3773–3779
with t-BuOMe (300 mL), and the combined extracts were washed
with H2O (3ꢁ200 mL) and brine (200 mL), dried (anhyd MgSO4),
and filtered. Removal of the solvent afforded a residue, which was
chromatographed using cyclohexane–ethylacetate (9.5:0.5) as el-
uent to give 19 (0.72 g, 48%) as a yellow oil. 1H NMR (400 MHz,
(2.8 g, 15 mmol) was added. Upon warming to ambient tempera-
ture the mixture is stirred for 14 h. The reaction mixture was
fractionated was with t-BuOMe (150 mL) and 1 M hydrochloric acid
(100 mL). The organic layer was washed with H2O (5ꢁ100 mL) and
brine (100 mL), dried (anhyd MgSO4), and concentrated under re-
duced pressure. The residue was chromatographed using cyclo-
hexane–ethylacetate (9:1) as eluent to give 23 (3.7 g, 86%) as
CDCl3):
d
¼1.06 (s, 9H), 2.75 (t, J¼8.0 Hz, 2H), 4.42 (t, J¼8.0 Hz, 2H),
6.72–6.75 (m, 2H), 6.77–6.79 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
¼24.21, 31.98, 40.41, 69.94, 107.60, 121.49, 148.14; MS (EI, 70 eV):
a colorless oil. 1H NMR (300 MHz, CDCl3):
1.06 (s, 9H), 1.13–1.32 (m, 4H), 2.97 (s, 2H), 3.83 (t, J¼7.1 Hz, 2H),
6.69–6.76 (m, 4H); 13C NMR (75 MHz, CDCl3):
d
¼0.82 (t, J¼6.5 Hz, 3H),
m/z (%)¼251.2 (14) [M]ꢃþ; HRMS: m/z calcd for C13H17NO4 [M]þ
251.1158, found 251.1159.
d
¼13.61, 18.94, 24.17,
30.16, 39.64, 40.76, 64.74, 107.35, 120.60, 120.87, 148.59, 168.89; MS
(EI): m/z (%)¼292.2 (15) [M]ꢃþ. Anal. Calcd for C17H24O4: C, 69.84; H,
8.27; Found: C, 69.81; H, 8.03.
4.21. 2-(Carboxylmethyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (20)
A solution of 8 (2.15 g, 8 mmol) in THF and H2O (3:1, 70 mL) was
treated with lithium hydroxide (0.6 g, 24 mmol) and stirred for 4
days at room temperature. The mixture was diluted with H2O,
acidified with 1 M hydrochloric acid (30 mL), and immediately
extracted with ethylacetate (100 mL). The organic layer was
washed several times with H2O (3ꢁ50 mL) and brine (50 mL), dried
(anhyd MgSO4), and filtered. Removal of the solvent gave acid 20
(1.40 g, 73%) as colorless needles. Mp 132–133 ꢀC; 1H NMR
4.25. 2-(1,1-Dimethylethyl)-2-(2-methoxyethoxy-
carbonylmethyl)benzo[1,3]dioxole (24)
To an ice cooled solution of 20 (2.3 g, 10 mmol) in dry CH2Cl2
(100 mL), N,N0-dicyclohexyl carbodiimide (2.2 g, 10 mmol) and
4-N,N-dimethylaminopyridine (0.13 g, 1 mmol) were added. The
reaction mixture was stirred for about 10 min and after that, 2-
methoxyethanol (0.9 g, 12 mmol) was added. On warming up on
ambient temperature the mixture is stirred for 14 h. The colorless
precipitate formed during the reaction is removed by filtration and
subsequently washed with (25 mL) cold CH2Cl2. The filtrate was
concentrated under reduced pressure. The residue was chromato-
graphed using cyclohexane–ethylacetate (8:2) as eluent to give 23
(300 MHz, CDCl3):
d
¼1.06 (s, 9H), 2.95 (s, 2H), 6.69–6.73 (m, 4H);
13C NMR (75 MHz, CDCl3):
d
¼24.19, 39.01, 40.86, 107.56, 120.22,
121.10, 148.31, 174.16; MS (ESþ): m/z¼259.1 [MþNa]þ; HRMS: m/z
calcd for C13H16NaO4 [MꢂNaþ] 259.0941, found 259.0950.
4.22. 2-(Carboxamidoylmethyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (21)
(2.4 g, 84%) as a colorless oil. 1H NMR (300 MHz, CDCl3):
d¼1.05 (s,
9H), 3.01 (s, 2H), 3.23 (dd, J¼4.4 Hz, 2H), 3.27 (s, 3H), 3.96 (dd,
J¼5.4 Hz, 2H), 6.69–6.76 (m, 4H); 13C NMR (75 MHz, CDCl3):
A solution of acid 20 (0.4 g, 1.7 mmol) in CH2Cl2 (10 mL) at room
temperature was treated with N,N0-dicyclohexyl carbodiimide
(0.35 g, 1.7 mmol) and the mixture was stirred for 1 h. 4-N,N-
Dimethylaminopyridine (0.02 g, 0.17 mmol) was added and the
stirring was continued for an additional 1 h. The reaction mixture
was treated with aqueous ammonia (3 mL). After being stirred
overnight, the mixture was filtered, then CH2Cl2 (50 mL) was added
to the filtrate. The organic layer was washed with H2O (3ꢁ50 mL),
Na2CO3 solution (50 mL), and brine (50 mL), dried (anhyd MgSO4),
and filtered. Removal of the solvent afforded a residue, which was
crystallized using cyclohexane to give 21 (0.27 g, 68%) as colorless
d
¼24.11, 39.31, 40.69, 58.73, 63.60, 69.82, 107.29, 120.52, 120.84,
148.60, 168.65; MS (EI): m/z (%)¼294.1 (20) [M]ꢃþ; Anal. Calcd for
C16H22O5: C, 65.29; H, 7.53; Found: C, 65.50; H, 7.55.
4.26. 2-(1,1-Dimethylethyl)-2-((methyloxycarbonylmethyl)-
oxycarbonylmethyl)benzo[1,3]dioxole (25)
To an ice cooled solution of 20 (4.3 g, 18 mmol) in dry DMF
(75 mL) was added NaH (0.76 g, 60%, 19 mmol). The reaction mix-
ture is stirred until evolution of gas ceased, bromoacetatemethyl
ester (2.9 g, 19 mmol) and NaI (0.3 g, 2 mmol) were added. Upon
warming to ambient temperature the mixture is stirred for 16 h.
The reaction mixture was fractionated was with t-BuOMe (200 mL)
and 1 M hydrochloric acid (100 mL). The organic layer was washed
with H2O (5ꢁ100 mL) and brine (100 mL), dried (anhyd MgSO4),
and concentrated under reduced pressure. The residue was chro-
matographed using cyclohexane–ethylacetate (8:2) as eluent to
give 25 (5.0 g, 89%) as a colorless oil. 1H NMR (300 MHz, CDCl3):
needles. Mp 100–101 ꢀC; 1H NMR (400 MHz, CDCl3):
2.89 (s, 2H), 5.97 (br, 2H), 6.73–6.76 (m, 4H); 13C NMR (100 MHz,
d¼1.07 (s, 9H),
CDCl3):
d
¼24.36, 40.92, 41.13, 107.92, 121.11, 121.41, 148.00, 170.39;
MS (EI, 70 eV): m/z (%)¼235.1 (28) [M]ꢃþ. Anal. Calcd for C13H17NO3:
C, 66.36; H, 7.28; N, 5.95. Found: C, 66.45; H, 7.35; N, 6.06.
4.23. 2-(Cyanomethyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (22)
d
¼1.07 (s, 9H), 3.09 (s, 2H), 3.68 (s, 3H), 4.36 (s, 2H), 6.70–6.77 (m,
4H); 13C NMR (75 MHz, CDCl3):
d
¼24.17, 38.74, 40.72, 52.12, 60.73,
To a solution of the amide 21 (0.117 g, 0.5 mmol) in pyridine
(10 mL), 4-toluenesulfonyl chloride (0.2 g, 1 mmol) is added. The
reaction mixture was stirred overnight at rt, poured onto ice water.
The solid was filtered off, washed by water (50 mL) to give nitrile 22
(0.96 g, 88%) as colorless powder. Mp 91–92 ꢀC; 1H NMR (400 MHz,
107.41, 120.35, 120.98, 148.46, 167.83, 167.95; MS (EI): m/z
(%)¼308.2 (12) [M]ꢃþ. Anal. Calcd for C16H20O6: C, 62.33; H, 6.54;
Found: C, 61.97; H, 6.76.
4.27. 2-(2-Chloroethoxycarbonylmethyl)-2-(1,1-dimethyl-
ethyl)benzo[1,3]dioxole (26)
CDCl3):
d
¼1.11 (s, 9H), 2.98 (s, 2H), 6.8–6.83 (m, 4H); 13C NMR
(100 MHz, CDCl3):
d
¼24.00, 24.29, 40.09, 108.23, 115.28, 118.55,
121.80, 147.50; MS (EI, 70 eV): m/z (%)¼217.1 (24) [M]ꢃþ; HRMS: m/z
To an ice cooled solution of 20 (4.5 g, 19 mmol) in dry DMF
(100 mL) was added NaH (0.77 g, 60%, 19 mmol). The reaction
mixture is stirred until evolution of gas ceased, 1,2-dichloroethane
(18.8 g, 190 mmol) was added. Upon warming to ambient temper-
ature the mixture is stirred for 16 h. The reaction mixture was
fractionated with t-BuOMe (200 mL) and 1 M hydrochloric acid
(100 mL). The organic layer was washed with H2O (5ꢁ100 mL) and
brine (100 mL), dried (anhyd MgSO4), and concentrated under
reduced pressure. The residue was chromatographed using
calcd for C13H15NO2 [M]þ 217.1103, found 217.1102.
4.24. 2-(Butoxycarbonylmethyl)-2-(1,1-dimethylethyl)-
benzo[1,3]dioxole (23)
To an ice cooled solution of 20 (3.5 g, 15 mmol) in dry DMF
(75 mL), NaH (0.62 g, 60%, 15 mmol) was added. The reaction
mixture is stirred until evolution of gas ceased. Then, n-butyliodide

N.M. Boshta et al. / Tetrahedron 65 (2009) 3773–3779
3779
cyclohexane–ethylacetate (9:1) as eluent to give 26 (3.4 g, 59%) as
a colorless oil. 1H NMR (300 MHz, CDCl3):
¼1.07 (s, 9H), 3.02 (s,
2H), 3.22 (t, J¼6.1 Hz, 2H), 4.06 (t, J¼6.1 Hz, 2H), 6.72–6.77 (m, 4H);
13C NMR (75 MHz, CDCl3):
107.43, 120.52, 121.03, 148.52, 168.40; MS (EI): MS (EI): m/z
(%)¼298.2 (16) [M]ꢃþ; HRMS: m/z calcd for C15H19ClNaO4 [MꢂNaþ]
321.0864, found 321.0867.
References and notes
d
1. (a) Hoeltke, C.; von Wallbrunn, A.; Kopka, K.; Schober, O.; Heindel, W.; Schae-
fers, M.; Bremer, C. Bioconjugate Chem. 2007, 18, 685; (b) Raitio, K. H.; Savi-
nainen, J. R.; Vepsaelaeinen, J.; Laitinen, J. T.; Poso, A.; Jaervinen, T.; Nevalainen,
T. J. Med. Chem. 2006, 49, 2022; (c) Doherty, A. M.; Patt, W. C.; Edmunds, J. J.;
Berryman, K. A.; Reisdorph, B. R.; Plummer, M. S.; Shahripour, A.; Lee, C.; Cheng,
X.; Walker, D. M.; Haleen, S. J.; Keiser, J. A.; Flynn, M. A.; Welch, K. M.; Hallak, H.;
Taylor, D. G.; Reynolds, E. E. J. Med. Chem. 1995, 38, 1259; (d) Chan, G. W.; Mong,
S.; Hemling, M. E.; Freyer, A. J.; Offen, P. H.; DeBrosse, C. W.; Sarau, H. M.;
Westley, J. W. J. Nat. Prod. 1993, 56, 116.
d
¼24.13, 39.40, 40.62, 40.73, 64.19,
4.28. 2-(1,1-Dimethylethyl)-2-(N-morpholinocarbonyl-
2. (a) Suzuki, M.; Nishida, Y.; Ohguro, Y.; Miura, Y.; Tsuchida, A.; Kobayashi, K.
Tetrahedron: Asymmetry 2004, 15, 159; (b) Nishida, Y.; Suzuki, M.; Kobayashi, K.;
Toriumi, Y.; Hashimoto, H. Anal. Sci. 2001, 17, 685; (c) Ami, E.; Ohrui, H. Biosci.
Biotechnol. Biochem. 1999, 63, 2150; (d) Sato, S.; Shimizu, K.; Kim, J.; Ami, E.;
Akasaka, K.; Ohrui, H. Chromatography 1999, 20, 71; (e) Shimizu, K.; Kim, J.;
Akasaka, K.; Ohrui, H. Chirality 1999, 11, 149; (f) Sato, S.; Shimizu, K.; Kim, J.;
Ami, E.; Akasaka, K.; Ohrui, H. Biosci. Biotechnol. Biochem. 1998, 62, 1822; (g)
Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasu-
moto, T. J. Am. Chem. Soc. 1997, 119, 11325; (h) Nishida, Y.; Kim, J.; Ohrui, H.;
Meguro, H. J. Am. Chem. Soc. 1997, 119, 1484; (i) Kim, J.; Uzawa, H.; Nishida, Y.;
Ohrui, H.; Meguro, H. J. Chromatogr., A 1994, 677, 35; (j) Nishida, Y.; Bai, C.;
Ohrui, H.; Meguro, H. J. Carbohydr. Chem. 1994, 13, 1003; (k) Nishida, Y.; Ohrui,
H.; Meguro, H. Tetrahedron Lett. 1989, 30, 5277.
3. (a) Review: Meguro, H.; Kim, J.-H.; Bai, C.; Nishida, Y.; Ohrui, H. Chirality 2001,
13, 441; (b) Suzuki, M.; Nishida, Y.; Ohguro, Y.; Kobayashi, K. Heterocycles 2005,
65, 1051; (c) Suzuki, M.; Ohguro, Y.; Kobayashi, K.; Nishida, Y. Heterocycles 2005,
65, 2395; (d) Dohi, H.; Nishida, Y.; Mizuno, M.; Shinkai, M.; Kobayashi, T.;
Takeda, T.; Uzawa, H.; Kobayashi, K. Bioorg. Med. Chem. 1999, 7, 2053; (e) Shi-
mizu, K.; Ohrui, H.; Meguro, H. Chromatography 1997, 18, 116; (f) Bai, C.; Ohrui,
H.; Nishida, Y.; Meguro, H. Anal. Biochem. 1997, 246, 246; (g) Itoh, E.; Nishida, Y.;
Togashi, Y.; Ohrui, H.; Meguro, H. Anal. Sci. 1996, 12, 551; (i) Bai, C.; Nishida, Y.;
Ohrui, H.; Meguro, H. J. Carbohydr. Chem. 1996, 15, 217; (j) Nishida, Y.; Itoh, E.;
Abe, M.; Ohrui, H.; Meguro, H. Anal. Sci. 1995, 11, 213; (k) Kim, J.; Nishida, Y.;
Ohrui, H.; Meguro, H. J. Chromatogr., A 1995, 709, 375; (l) Kim, J.; Nishida, Y.;
Ohrui, H.; Meguro, H. J. Carbohydr. Chem. 1995, 14, 889.
methyl)benzo[1,3]dioxole (27)
In a 25 mL one-necked flask, 8 (2.5 g, 10 mmol) was dissolved in
10 mL morpholine. The mixture was heated to reflux for about 48 h.
After concentration under reduced pressure, the resulting oil was
fractionated with t-BuOMe (150 mL) and 1 M hydrochloric acid
(30 mL). The organic layer was washed with H2O (5ꢁ100 mL) and
brine (100 mL), dried (anhyd MgSO4), and concentrated under re-
duced pressure. The residue was chromatographed using cyclo-
hexane–ethylacetate (1:1) as eluent to give 27 (2.1 g, 70%) as
a colorless solid. 1H NMR (400 MHz, CDCl3):
2H), 3.36–3.42 (m, 4H), 3.48–3.63 (m, 4H), 6.73–6.77 (m, 4H); 13C
NMR (100 MHz, CDCl3):
d
¼1.09 (s, 9H), 3.04 (s,
d
¼24.19, 37.41, 40.73, 41.89, 47.29, 66.35,
66.55, 107.54, 121.11, 121.54, 148.00, 166.48; MS (EI): m/z (%)¼305.2
(22) [M]ꢃþ; HRMS: m/z calcd for C17H23NNaO4 [MꢂHþ] 328.1519,
found 328.1513.
4.29. 2-(2-N,N-Diethylcarboxamidomethyl)-2-(1,1-
dimethylethyl)benzo[1,3]dioxole (28)
4. (a) Waldvogel, S. R.; Wartini, A. R.; Rasmussen, P. H.; Rebek, J., Jr. Tetrahedron Lett.
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To an ice cooled solution of 20 (3.4 g, 14 mmol) in dry CH2Cl2
(100 mL), N,N0-dicyclohexyl carbodiimide (3.0 g, 14 mmol) and 4-
N,N-dimethylaminopyridine (0.173 g, 1.4 mmol) were added. The
reaction mixture was stirred for about 10 min and after that,
diethylamine (2.0 g, 28 mmol) was added. Upon warming to am-
bient temperature the mixture is stirred for 14 h. The colorless
precipitate formed during the reaction is removed by filtration
and washed with (25 mL) cold CH2Cl2. The solvent was concen-
trated under reduced pressure. The residue was chromatographed
using cyclohexane–ethylacetate (1:1) as eluent to give 28 (2.35 g,
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and references cited therein.
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1443; (b) Bomkamp, M.; Artiukhov, A.; Kataeva, O.; Waldvogel, S. R. Synthesis
2007, 1107.
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Org. React. 1974, 21, 125.
55%) as a colorless solid. 1H NMR (400 MHz, CDCl3):
d
¼0.58 (t,
J¼7.0 Hz, 3H), 1.09 (s, 9H), 1.12 (t, J¼7.0 Hz, 3H), 3.15 (q, J¼7.0 Hz,
2H), 3.39 (q, J¼7.0 Hz, 2H), 6.73–6.78 (m, 4H); 13C NMR (100 MHz,
CDCl3):
d
¼11.80, 13.78, 24.23, 37.49, 39.71, 40.51, 42.19, 107.42,
120.89, 121.53, 148.16, 166.97; MS (EI): m/z (%)¼291.2 (18) [M]ꢃþ
;
HRMS: m/z calcd for C17H26NO3 [MþHþ] 292.1907, found
292.1899.
16. Fernandez-Mateos, A.; Pascual Coca, G.; Rubio Gonzalez, R.; Tapia Hernandez, C.
J. Org. Chem. 1996, 61, 9097.
Acknowledgements
17. Ryu, H.; Jin, M.; Kim, S.; Choi, H.; Kang, S.; Kang, D. W.; Lee, J.; Pearce, L. V.;
Pavlyukovets, V. A.; Morgan, M. A.; Tran, R.; Toth, A.; Lundberg, D. J.; Blumberg,
P. M. J. Med. Chem. 2008, 51, 57.
18. Stephens, C. R.; Bianco, E. J.; Pilgrim, F. J. J. Am. Chem. Soc. 1955, 77, 1701.
19. Franz, J. A.; Martin, J. C. J. Am. Chem. Soc. 1973, 95, 2017.
The work was supported by the SFB 624 (German Research
Foundation) and by the Egyptian Government with a stipend for
N.M.B. (Channel program).