A new method for the synthesis of mixed orthoesters from O-allyl acetals

Article abstract of DOI:10.1016/j.tetlet.2008.12.110

Two new methods for the synthesis of orthoesters and compounds containing an orthoester moiety (dihydroisoxazoles) are presented. Mixed orthoesters of general formulas RC(OR¹)(OR²)₂ and RC(OR¹)(OR²)(O

Full text of DOI:10.1016/j.tetlet.2008.12.110

Tetrahedron Letters 50 (2009) 1193–1195
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A new method for the synthesis of mixed orthoesters from O-allyl acetals
a
a
a
a
a
Stanisław Krompiec a, , Robert Penczek , Piotr Bujak , Ewelina Kubik , Joanna Malarz , Mateusz Penkala ,
*
a
b
c
´
Michał Krompiec , Nikodem Kuznik , Hieronim Maciejewski
a Institute of Chemistry, Faculty of Mathematics, Physics and Chemistry, University of Silesia ul. Szkolna 9, 40-007 Katowice, Poland
b Faculty of Chemistry, Silesian University of Technology, ul. B. Krzywoustego 4, 44-100 Gliwice, Poland
c Faculty of Chemistry, Adam Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new methods for the synthesis of orthoesters and compounds containing an orthoester moiety
(dihydroisoxazoles) are presented. Mixed orthoesters of general formulas RC(OR1)(OR2)2 and RC(OR1)-
(OR2)(OR3) were prepared via addition of ROH (R = Bu or m-methylphenyl) to O-allyl acetals (acrolein
acetals: diethyl or cyclic, i.e., 2-vinyl-1,3-dioxanes or dioxolanes). The catalytic systems for these reac-
tions were generated from [RuCl2(PPh3)3] and Na2CO3; {[RuCl2(COD)]x} or {[OsCl2(1,5-COD)]x}, PPh3,
and Na2CO3. Compounds containing an orthoester moiety (dihydroisoxazoles) were prepared via tandem
isomerization of O-allyl acetals (to O-vinyl acetals) catalyzed by ruthenium complexes followed by cyclo-
addition to in situ-generated 2,6-dichlorophenylnitrile oxide.
Received 14 October 2008
Revised 16 December 2008
Accepted 22 December 2008
Available online 8 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
R1
Orthoesters are well-known compounds, and have many appli-
cations. They are used in organic synthesis as protected forms of
carboxylic acids,1–3 as endosome permeation agents,4,5 as deter-
gents,6,7 and in polymer synthesis.8 The synthesis of symmetric
orthoesters (formally, acetals of esters) is simple and well known.
A selective synthesis of mixed orthoesters of the general types
RC(OR1)(OR2)2 and RC(OR1)(OR2)(OR3) has not been described pre-
viously. The synthetic methods described in the literature always
lead to the formation of a mixture of all the possible symmetric
and mixed orthoesters. Herein, we describe two routes for the syn-
thesis of mixed orthoesters from O-allyl acetals (particularly, cyclic
or acyclic acetals of acrolein). The first route for the synthesis of
mixed orthoesters involves the addition of ROH (1-butanol or
m-cresol) to acrolein acetals, for example, acrolein cyclic acetal,
Scheme 1. The most effective catalysts for this transformation were
ruthenium complexes and an osmium complex generated in situ
from {[OsCl2(1,5-COD)]x} and PPh3.
Conversion of the allylic systems was practically quantitative,
and reaction selectivity was excellent. All possible stereoisomers
of the orthoesters were formed. The structures of the orthoesters
prepared from 2-vinyldioxanes and 2-vinyldioxolanes (acrolein
cyclic acetals) are presented in Figure 1.
Previously, we found that the catalytic systems generated
in situ from Ru or Os complexes, external ligands (particularly,
phosphines), and base (Na2CO3, t-BuOK) were very effective for
the addition of ROH to allyl ethers.9 It is worth emphasizing that
O
R1
[Ru]
O
+
1.5 ROH
120 °C; 3 h
O
O
OR
Scheme 1. Synthesis of mixed orthoesters via addition of 1-butanol or m-cresol to
O-allyl acetals catalyzed by 1% mol [RuCl2(PPh3)3] and 5% mol Na2CO3.
the precursors (for example, [Ru3(CO)12], {[RuCl2(COD)]x}) used
without additives were active, while the addition of base increased
the selectivity by suppressing transacetalization. In the present
work, we investigated the activity of several catalytic systems
studied previously for the synthesis of acetals9 in the model
addition reaction of m-cresol to 5,5-dimethyl-2-vinyl-1,3-dioxane
(see Scheme 2 and Table 1).
O
O
O
O
OR
OR
R = 3-methylphenyl (84%; 3 h)
R = butyl (88%; 4 h)
R = 3-methylphenyl (86%; 4 h)
R = butyl (87%; 4 h)
O
O
O
O
OBu
OBu
O
O
OR
R = 3-methylphenyl (81%; 3 h)
R = butyl (82%; 3 h)
(88%; 4 h)
(78%; 4 h)
* Corresponding author. Tel.: +4832 3591646, fax: +4832 2599978.
E-mail addresses: stanislaw.krompiec@gmail.com, robert.penczek@gmail.com
(S. Krompiec).
Figure 1. The structures of the orthoesters synthesized from 2-vinyldioxanes and
2-vinyldioxolanes according to Scheme 1 (isolated yields and reaction times are
given in parentheses).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.110

1194
S. Krompiec et al. / Tetrahedron Letters 50 (2009) 1193–1195
N
Ar
OR1
O
O
O
OR1
OR2
O
[M]
ArCNO
1 mol% [Ru]-H
THF
OR1
OR2
+ 1.5
OH
120 °C, 3 h
O
O
OR2
[Ru]-H = [RuClH(CO)(PPh3)3]; R1, R2 = alkyl; Ar = 2,6-dichlorophenyl
Scheme 2. Addition of m-cresol to 5,5-dimethyl-2-vinyl-1,3-dioxane catalyzed by
ruthenium and osmium complexes ([M]) with Na2CO3.
Scheme 4. One-pot tandem isomerization (of O-allyl acetals to O-vinyl acetals)—
1,3-dipolar cycloaddition (nitrile oxide to O-vinyl acetals).
Table 1
Catalytic systems for the addition of m-cresol to 5,5-dimethyl-2-vinyl-1,3-dioxane.
COD—1,5-cyclooctadiene (120 °C, 3 h, without solvent)
N
Ar
O
N
[M]a
Yieldb (%)
Ar
Entry
N
Ar
O
O
O
1
2
3
4
5
6
7
8
[RuCl2(PPh3)3]
{[RuCl2(1,5-COD)]x}
{[RuCl2(1,5-COD)]x} + PPh3
{[RuCl2(1,5-COD)]x} + rac-BINAP
{[OsCl2(1,5-COD)]x}
94
0
94
0
O
O
OC2H5
OC2H5
O
0
(80%)
(87%)
Ar
(78%)
{[OsCl2(1,5-COD)]x} + PPh3
96
44
0
[Ru3(CO)12
]
[Ru3(CO)12] + 3PPh3
N
O
a
N
Ar
All catalytic systems contained 5 mol % Na2CO3.
Yield determined by 1H NMR spectroscopy.
O
O
b
O
O
O
The results were quite different from those obtained in the
addition of ROH to allyl ethers leading to acetals.9 The polymeric
complexes of Ru and Os (entries 2 end 6) were highly active in
the synthesis of acetals, but in the synthesis of orthoesters they
were inactive unless triphenylphosphine was added. Furthermore,
the system {[RuCl2(1,5-COD)]x}/rac-BINAP/Na2CO3 was not active
for orthoester synthesis, while it catalyzed the acetalization of allyl
ethers very effectively.9 In contrast to the polymeric precursors,
(82% )
(80%)
Figure 2. Structures of the dihydroisoxazoles containing an orthoester moiety
synthesized according to Scheme 4 (isolated yields in parentheses).20,21
Ar
N
OR1
OR2
O
[Ru3(CO)12] catalyzed the addition poorly, and the system
ArCNO
[Ru3(CO)12]/3PPh3/5Na2CO3 was not active at all. On the other
hand, both [Ru3(CO)12] and [Ru3(CO)12]/3PPh3/base were very ac-
tive catalysts in the addition of ROH to allyl ethers.9 We conclude
that the addition of ROH to cyclic acrolein acetals is much more
sensitive to steric hindrance than the synthesis of acetals from allyl
ethers. It seems that the polymeric complexes of Ru and Os and the
complexes formed from {[RuCl2(1,5-COD)]x} and rac-BINAP or
[Ru3(CO)12] with PPh3 are too bulky, hence the reaction does not
take place.
We carried out a test reaction in order to prove our hypothesis
of steric hindrance as a limiting factor, which involved the addition
of n-BuOH to the diethyl acetal of acrolein. This reaction proceeded
quantitatively at 80 °C, Scheme 3. Replacement of the rigid 2-vinyl-
dioxane or dioxolane cyclic systems with a much more flexible
acyclic acetal eliminates steric hindrance, thus lowering the activa-
tion energy.
Using the same O-allyl acetals, we synthesized a series of dihyd-
roisoxazoles containing an orthoester moiety via tandem isomeriza-
tion (O-allyl acetals to O-vinyl acetals) cycloaddition (nitrile oxide to
O-vinyl acetals), see Scheme 4. This novel approach enables the
synthesis of new functionalized dihydroisoxazoles. Many isoxazo-
lines10–13 and their aromatic homologs and analogs, that is, isoxaz-
oles14,15 serve as drugs or as potential drugs with, for example,
anti-inflammatory,16 antiplatelet17, or antidepressant18 activity.
Ar = 2,6-Cl2C6H3
OR1
R2 O
Scheme 5. 1,3-Dipolar cycloaddition of 2,6-dichlorobenzonitrile oxide to O-allyl
acetals.
It is important to note that as in the cycloaddition of nitrile oxi-
des to O-vinyl ethers,19 the reaction is completely regioselective:
orthoesters are the only products. The alternative regioisomer,
the acetal did not form at all. The structures of the 4,5-dihydrois-
oxazoles synthesized according to Scheme 4 are presented in
Figure 2.
We checked whether the appropriate O-allyl systems would
cyclize; however the dihydroisoxazoles formed do not belong to
the orthoester class.
New possibilities of the application of O-allyl acetals for the
synthesis of dihydroizoxazoles are described. In the tandem
reaction: isomerization of O-allyl acetals (to O-vinyl acetals)—1,3-
cycloaddition (of a nitrile oxide to the O-vinyl acetals), dihydroxaz-
oles, which are formally orthoesters, are formed. On the other
hand, in the 1,3-cycloaddition of a nitrile oxide to O-allyl acetals,
dihydroisoxazoles containing an acetal group are formed (see
Scheme 5).
Acknowledgments
[Ru]
OBu
OEt
BuOH
1.5
+
80 °C; 3 h
This work was supported by the Ministry of Science and Higher
Education, Project No. 3 T09A 147 29. R. Penczek and M. Krompiec
gratefully acknowledge scholarships from the UPGOW project
co-financed by the European Social Fund.
EtO
EtO
OEt
Scheme 3. Addition of 1-butanol to acrolein diethyl acetal catalyzed by 1 mol %
[RuCl2(PPh3)3] and Na2CO3 (80 °C, 3 h without any solvent).

S. Krompiec et al. / Tetrahedron Letters 50 (2009) 1193–1195
1195
obtained solution of 2,6-dichlorobenzohydroximoyl chloride in CH2Cl2 was
added to the isomerization product, at 0–5 °C, followed by dropwise addition of
a solution of triethylamine (3.9 mmol) in CH2Cl2 (at 0–5 °C). The mixture was
stirred for 24 h at room temperature. The reaction mixture was washed with
water (3 Â 10 ml), dried over Na2SO4, and dissolved in hexane or in benzene–
hexane mixture. The resulting solution was passed through a short column
filled with amino functionalized mesoporous silica-foam (1 g MCF per 20 mg of
Ru-complex), and the ruthenium complexes were quantitatively adsorbed.
Isoxazolines–orthoesters were eluted with hexane or benzene-hexane
mixtures. The volatile fractions were evaporated on a rotary evaporator, and
pure products were obtained.Addition of ROH to O-allyl acetals: 2-Vinyl-1,3-
dioxane, 2-vinyl-1,3-dioxolane or acrolein diethyl acetal, ROH (1-butanol,
m-cresol), catalyst (1 mol %), and Na2CO3 (5 mol %) in a glass screw-capped
ampoule, purged with argon, then tightly capped, were heated in an oil bath for
the given period of time. Molar ratios of the reaction mixture components and
the temperatures are shown in Figure ure1 and Schemes 1–3. The orthoester
products were separated by distillation. When ROH was m-cresol, the excess
was removed, before distillation, by extraction with 1 M NaOH.
References and notes
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.;
Wiley: New York, 1991. pp 267–269.
2. Houben-Weyl. Methoden der organischen Chemie, IV Auflage, Georg Thieme:
Stuttgart, Bd. E5/1, S, 1995; pp 1–192.
3. Kocienski, P. J. Protecting Groups; Georg Thieme: Stuttgart, 1994.
4. Chen, H.; Zhang, H.; McCallum, C. M.; Szoka, F. C.; Guo, X. J. Med. Chem. 2007,
50, 4269–4278.
5. By, K.; Nantz, M. H. Angew. Chem., Int. Ed. 2004, 43, 1117–1120.
6. Mohlin, K.; Holmberg, K. J. Colloid Interface Sci. 2006, 299, 435–442.
7. Hellberg, P.-E. J. Surfact. Deterg. 2002, 5, 217–227.
8. Koppes, M. J.; van der Arend, J.; 1993, U.S. 5,194,535; Chem. Abstr. 1993, 119,
9343x.
9. Krompiec, S.; Penczek, R.; Penkala, M.; Krompiec, M.; Rzepa, J.; Matlengiewicz,
M.; Jaworska, J.; Baj, S. J. Mol. Catal. A: Chem. 2008, 290, 15–22.
10. Mzengeza, S.; Whitney, R. A. J. Org. Chem. 1988, 53, 4074–4081.
11. Weidner-Wells, M. A.; Fruga-Spano, S. A.; Turchi, I. J. J. Org. Chem. 1998, 63,
6319–6328.
21. Selected spectral data: 3-(2,6-Dichlorophenyl)-4-methyl-1,6,10-trioxa-2-
azaspiro[4.5]dec-2-ene: IR (film) 3061, 2979, 2933, 2862, 1734, 1560, 1432,
1148, 788, 741. HRMS (FAB): calcd for C13H14NO3Cl2 (M+H)+ 302.035074;
found, 302.03508. 1H NMR (400 MHz, CDCl3) d = 1.05 ppm (d, J = 7.1 Hz, 3H,
CH3CH); 1.79 (t, J = 5.9 Hz, 2H, CH2CH2CH2); 3.61 (t, J = 5.9 Hz, 2H, CH2CH2CH2);
4.15 (t, J = 6.0 Hz, 2H, CH2CH2CH2); 4.37 (q, J = 7.1 Hz, 1H, CH3CH); 7.26–7.32
12. Batt, D. G.; Hughton, G. C.; Daneker, W. F.; Jadhav, P. K. J. Org. Chem. 2000, 65,
8100–8104.
13. Pinto, A.; Conti, P.; Amici, M.; Tamborini, L.; Madsen, U.; Christesen, T.;
Bräuner-Osborne, H.; Micheli, T. J. Med. Chem. 2008, 51, 2311–2315.
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B.; Ehrbar, U.; Olesen, P. H. J. Med. Chem. 1999, 42, 4970–4980.
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6074.
20. Standard reaction procedure. Isomerization of allyl systems: Isomerization was
carried out in screw-capped ampoules, under an argon atmosphere: a mixture
of allyl substrate (3 mmol), catalyst (1 mol % [RuClH(CO)(PPh3)3]), and THF
(1 cm3 per 1 mmol) was stirred for a given period of time (2–4 h). After cooling,
the solvent was evaporated and the residue was used in the cycloaddition
reaction without additional purification. Cycloadditions: To a stirred solution of
1.3 mmol of 2,6-dichlorobenzaldoxime in 10 ml of CH2Cl2 at room
temperature, 1.4 mmol of solid NCS was added. The reaction was initiated by
the addition of one drop of conc. hydrochloric acid. After stirring for 4 h, the
(m, 3H, CAr-H
(OCH2CH2CH2O); 52.0 (CH3CH); 61.3 (OCH2CH2CH2O); 120.5 (CH3CHC); 159.2
(C@N); 129.6; 131.3; 132.4; 135.6 (CAr) MS (ESI) m/z 329.1 [M+4H+Na]2+
)
13C NMR (100 MHz, CDCl3) d = 12.8 ppm (CH3CH); 25.2
.
2-Butoxy-2-ethyl-5,5-dimethyl-1,3-dioxane: IR (film) 2957, 2875, 2734, 1744,
1469, 1364, 1251, 1211, 1149, 1072. CHN: calcd for C12H24O3: C, 66.63; H,
11.18. Found: C, 66.58; H, 11.21. 1H NMR (CDCl3, 600 MHz) d = 1.16 (s, 3H, –
CH3), 0.95 (t, J = 7.3 Hz, 3H, –CH2CH3), 0.96 (t, J = 7.5 Hz, 3H,
–
OCH2CH2CH2CH3), 1.16 (s, 3H, –CH3), 1.41–1.47 (m, 2H, –OCH2CH2CH2CH3),
1.58–1.63 (m, 2H, –OCH2CH2CH2CH3), 1.75 (q, J = 7.5 Hz, 2H, –CH2CH3), 3.24 (d,
J = 10.4 Hz, 6.6 Hz, 2H, –OCHaHbC(CH3)2CHaHbO–), 3.40 (t, J = 6.6 Hz, 2H, –
OCH2CH2CH2CH3), 3.80 (d, J = 10.4 Hz, 2H, –OCHaHbC(CH3)2CHaHbO–). 13C NMR
(CDCl3, 150 MHz) d = 7.4 (–OCH2CH3), 14.0 (–OCH2CH2CH2CH3), 19.7
(–OCH2CH2CH2CH3), 22.1 (–CH3), 22.7 (–CH3), 28.5 (–CH2CH3), 29.1
(–OCH2CH2CH2O–), 32.0 (–OCH2CH2CH2CH3), 62.0 (–OCH2CH2CH2CH3), 69.7
(–OCH2CH2CH2O–), 111.9 (CIV). GC–MS (70 eV), m/z (int [%]): 216 (<1), 187 (6),
144 (12), 143 (69), 131 (60), 75 (70), 69 (52), 56 (100).