Lewis Acid-Catalyzed Additions of (Benzotriazol-1-yl)diethoxymethane to Enol Ethers and Enamides. New Syntheses of β-Alkoxyalkanal and β-Aminoalkanal Acetals

Article abstract of DOI:10.1021/jo9612335

Addition of (benzotriazol-1-yl)diethoxymethane 11 to various acyclic and cyclic enol ethers and enamides produces the corresponding adducts, which were reacted with either NaAlH₄ or Grignard reagents to afford acyclic acetal-ethers (18a-f), cyclic α-(substituted)-β-acetals (19a-c), amino-acetals (24a,b), and 1,3-amino-ethers (25), all known but previously difficult-to-access classes of compounds.

Full text of DOI:10.1021/jo9612335

700
J . Org. Chem. 1997, 62, 700-705
Lew is Acid -Ca ta lyzed Ad d ition s of
(Ben zotr ia zol-1-yl)d ieth oxym eth a n e to En ol Eth er s a n d En a m id es.
New Syn th eses of â-Alk oxya lk a n a l a n d â-Am in oa lk a n a l Aceta ls
Alan R. Katritzky,* Sergei A. Belyakov, Bogumila Rachwal, and J ean-Luc Moutou
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received J uly 1, 1996X
Addition of (benzotriazol-1-yl)diethoxymethane 11 to various acyclic and cyclic enol ethers and
enamides produces the corresponding adducts, which were reacted with either NaAlH4 or Grignard
reagents to afford acyclic acetal-ethers (18a -f), cyclic R-(substituted)-â-acetals (19a -c), amino-
acetals (24a ,b), and 1,3-amino-ethers (25), all known but previously difficult-to-access classes of
compounds.
Sch em e 1
In tr od u ction
Recent reports from our laboratory have described the
additions of 1-(R-alkoxybenzyl)benzotriazoles to enol
ethers which opened a new route to 1,3-diethers (Scheme
1),1 of 1-(R-aminoalkyl)benzotriazoles to enol ethers lead-
ing to 1,3-amino-ethers,2 and of 1-(R-aminoalkyl)benzo-
triazoles to N-vinyl amides to give unsymmetrically
substituted 1,3-diamines (Scheme 2).3,4 The benzotria-
zole-containing starting materials 1 and 5 (Schemes 1,
2) can be considered as protected oxonium (2) or immo-
nium (6) cations because of the easy heterolysis of the
C-Bt bond under mild acidic catalysis (p-toluenesulfonic
acid) and consequently react with enol ethers and en-
amides to form the corresponding benzotriazolyl-substi-
tuted addition products (c.f. 3, 7, 9). Replacement of the
benzotriazole moiety in 3, 7, 9 then gives the final 1,3-
diethers, 1,3-amino-ethers, or 1,3-diamines (c.f. 4, 8, 10).
We have now investigated similar Lewis acid-catalyzed
additions of (benzotriazol-1-yl)diethoxymethane to enol
ethers and enamides and have shown that the benzotri-
azole-substituted acetals thus obtained undergo further
transformations (Grignard reaction, reduction, followed
by another Grignard reaction, etc.) to provide direct and
efficient routes to a wide range of â-alkoxy- and â-amino-
alkanal acetals, and 1,3-amino-ethers.
Sch em e 2
(Benzotriazol-1-yl)diethoxymethane 11 (Scheme 3) was
readily prepared in good yield as a stable (shelf life more
than 8 months), colorless, viscous liquid by the reaction
of benzotriazole with ethyl orthoformate. The crude
product 11 usually contains ca. 5-10% of 1-ethylbenzo-
triazole as a byproduct, which can be removed by distil-
lation; however, this byproduct does not affect the further
reactions of 11, and we therefore used crude 11 in
subsequent transformations.
Rea ction s w ith En ol Eth er s. Acetal 11 reacted with
enol ethers 12a -c under catalysis by boron trifluoride,
p-toluenesulfonic acid, or zinc bromide to give the addi-
tion compounds 13a -c. These acid catalysts all work
well for each vinyl substrate. Data in the Experimental
Section simply underline the equality of the catalytic
effect of such Lewis acids in our reactions. The mecha-
nism of the reaction clearly involves the ionization of 11
followed by stepwise addition of the ion pair thus formed
to the double bond of enol ether (Scheme 3). The crude
products contained small amounts (5-9%) of ethers 14a -
c, as shown by NMR spectra.23 The formation of the
byproduct ethers 14 is explained by the addition to the
double bond of vinyl ether of free benzotriazole which
generated by reaction of ethanol with 11, the ethanol
being formed by elimination from 13a -c (compare with
formation of vinyl ethers from diacetals5,6 ). Compounds
13a -c were separated by column chromatography and
were characterized by NMR spectroscopy. However, the
presence of small amounts of 14a -c does not affect the
X Abstract published in Advance ACS Abstracts, J anuary 15, 1997.
(1) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J . J . Org.
Chem. 1992, 57, 4925.
(2) Katritzky, A. R.; Rachwal, S.; Rachwal, B.; Steel, P. J . J . Org.
Chem. 1992, 57, 4932.
(3) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J . Org. Chem. 1993,
58, 812.
(4) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J . Org. Chem. 1994,
59, 5206.
(5) Povarov, L. S. Russ. Chem. Rev. (Engl. Transl.) 1965, 34, 639.
(6) Mikhailov, B. M.; Povarov, L. S. J . Gen. Chem. USSR (Engl.
Transl.) 1959, 29, 2048.
S0022-3263(96)01233-9 CCC: $14.00 © 1997 American Chemical Society

Syntheses of â-Alkoxyalkanal and â-Aminoalkanal Acetals
J . Org. Chem., Vol. 62, No. 3, 1997 701
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
course of further chemical transformations of 13a -c, and
we therefore normally used the crude products 13a -c
for subsequent transformations.
acetal-ethers 18a -f were isolated either by column
chromatography (18a ,b,d -f) or by Kugelrohr distillation
(18c). NMR spectra of the compounds 18a -f do not
contain signals for a benzotriazolyl substituent, but
instead have the appropriate sets of the signals for the
corresponding R-substituents. No transformations of the
geminal diethoxy functionality with the Grignard re-
agents were detected in any of these reactions: in the
1H and 13C NMR spectra of all the acetal-ethers 18a -f
the signals for both geminal ethoxy substituents are
essentially unchanged from those in 13a -c.
Acetal 11 reacts similarly with cyclic enol ethers 15a ,b
to give 2-(benzotriazolyl)-3-(diethoxymethyl)tetrahydro-
furan (16a ) and 2-(benzotriazolyl)-3-(diethoxymethyl)-
tetrahydropyran (16b) in high yields (Scheme 4). The
crude products 16a ,b also contained compounds 17a ,b.
We separated one pure stereoisomer of acetal 16b,
namely erythro-2-(benzotriazol-1-yl)-3-(diethoxymethyl)-
tetrahydropyran, to assist with the complete assignment
of the NMR signals, since the spectrum of a crude
reaction mixture was complex. On the basis of HETCOR
results, we assigned doublets at 4.42 and 6.36 ppm in
the 1H NMR spectrum of the isolated isomer to the
protons at C(2) and at C(3′) positions of the pyran-acetal
system. Irradiation of the former proton during NOEDIF
experiment caused a ca. 10% resonance enhancement of
the C(3′) proton signal, which allowed assignment of the
isolated isomer as erythro. The coupling constant of the
proton adjacent to the C(3′) atom (acetal proton) is
characteristic (ca. 8.0 Hz), which was useful for the
assignment of the related compound, 19c (see below).
However, for further preparative work, we used the crude
product mixtures (16a /17a and 16b/17b) without separa-
tion at this stage.
Tr a n sfor m a t ion s of t h e â-(Diet h oxym et h yl)-r-
ben zotr ia zolyla lk yl Eth er s 13 a n d 16. The acetals
13a -e underwent Grignard reactions with various alkyl-,
aryl-, and alkynylmagnesium halides in refluxing toluene
with selective replacement of the benzotriazolyl group to
give the corresponding substituted acyclic acetal-ethers
18a-f (Scheme 5) and cyclic acetal-ethers 19a-c (Scheme
6). These reactions of the acyclic compounds 13a -c gave
crude reaction products containing 70-85% of the desired
acetal-ethers 18a -f, according to the NMR data. Pure
Formation of the five-membered cyclic acetal-ethers
19a ,b occurred stereoselectively to give only the threo-
isomers, i.e., the introduction of the bulky phenyl sub-
stituent proceeds in the less sterically hindered way. The
six-membered cyclic acetal-ether 19c was obtained as a
1:2 mixture of erythro- and threo-isomers, which were
separated by column chromatography. Assignment of the
1H NMR signals for both erythro- and threo-19c is
hindered by overlapping of the C(3) proton signals with
the signals for the one of CH2 groups. Nevertheless,
based on the results for compound 16b, the erythro-
configuration was assigned to the specimen of 19c with
1
a H NMR doublet located in the same position and with
the same coupling constant as 16b. Total yields of the
cyclic acetal-ethers were above 80% (based on the NMR
of reaction mixtures) for all the compounds 19a -c.
Diethyl acetals 18, 19 are unstable compounds and
readily decompose during column chromatography. There-
fore, isolated yields given for these compounds in the
Experimental Section are substantially lower than those
estimated from the NMR. However, as shown on the
examples of the amino-acetals 24a ,b, larger than pre-
parative amounts of such acetals might be successfully
purified by distillation.

702 J . Org. Chem., Vol. 62, No. 3, 1997
Katritzky et al.
Sch em e 7
Grignard reaction of the acetal 24b with PhMgBr in
refluxing toluene after 5 h afforded the corresponding
substituted amino-ether 25 in 60% yield. In the 1H NMR
spectrum of 25 a new multiplet at ca. 7.27 ppm appeared,
and the integration of the signals of ethoxy group was
decreased, matching a calculation for three and two
protons, respectively, thus confirming the successful
displacement of one of the acetal ethoxy groups. Dis-
placement of one of the oxygens (ethoxy group) by carbon
(phenyl ring) resulted in the upfield shift of the signal of
ethereal R-carbon atom (from 101.6 to 80.4 ppm) in the
13C NMR spectrum of the amino-ether 25. Manipulations
with the type of substituents in the starting vinyl amides
21 and in Grignard reagents thus open the possibility to
vary substantially the structure of the amino-ethers 25.
Com p a r ison w it h P r eviou s Wor k . Mayr and co-
workers7 synthesized variously substituted propanal
dimethyl acetals and investigated systematically the
reactions of acetals and ortho esters with vinyl methyl
ether, concluding the following order of reactivity: form-
aldehyde acetals < aliphatic acetals < ortho esters <
aromatic acetals ) unsaturated aliphatic acetals. The
addition of ortho esters to enol ethers has significant
synthetic value since the final 1,1,3,3-tetraalkoxypro-
panes are malonaldehyde equivalents and are widely
used in the heterocyclic chemistry. They are com-
mercially available products but are usually manufac-
tured by other methods (see e.g. lit.8). By contrast, the
addition of either acetals or ortho esters to enamides has
not been previously studied.
An advantage of our new methodology is that the
acetals 13 are inactive toward competitive addition to
enol ethers: in all the cases we used acetal and vinyl
ether in equimolar ratio and did not observe the forma-
tion of any secondary addition products, while previously
described reactions of stoichiometric amounts of acetals
and enol ethers led to the formation of oligomers.5,9 This
difference in the reactivity patterns in acetals and 11
becomes crucial as far as their reactions with cyclic enol
ethers are concerned. Substituted tetrahydrofurans and
tetrahydropyrans are the structural subunits in naturally
occurring polyether antibiotics, pheromones, etc.10,11 Ad-
ditions of acetals to dihydrofurans and dihydropyrans
were previously found to yield the corresponding 2-alkoxy-
3-(R-alkoxy)alkyltetrahydrofurans or -pyrans;5,12,13 how-
ever, these reactions are often complicated by the for-
mation of secondary condensation products.
Sch em e 8
We prepared threo-2-phenyl-1,2,3,4-tetrahydrofuran-
3-carboxaldehyde 2,4-dinitrophenylhydrazone (20) in 72%
yield by reacting the cyclic acetal-ether 19a with 2,4-
dinitrophenylhydrazine in refluxing acetic acid.
R ea ct ion s w it h E n a m id es. Addition of boron tri-
fluoride etherate to a neat mixture of acetal 11 and
enamides 21a or 21b at 20 °C (Scheme 7) produces in
high yield the amido-acetals 22a and 22b, respectively,
each admixed with the corresponding amide 23a ,b (ca.
5-12%), similar to the reactions involving enol ethers.
Yields were based on NMR of the crude mixtures. We
isolated and characterized the individual amido-acetal
22b as a solid; however, as in the case of ether-acetals
13a -c, we used 22a with its minor impurities of 23a for
the further reactions, because reduction of the contami-
nant 23a gives a volatile product easily removable by
distillation or column chromatography. Compound 22a
was characterized by the 13C NMR data (see Experimen-
tal Section).
Reductions of amido-acetals 22a ,b with NaAlH4 in
THF at 20 °C afforded the corresponding â-amino alde-
hyde ethyl acetals 24a ,b in good yields (82% and 92%,
respectively) as a result of reduction of amido group and
simultaneous substitution of benzotriazole moiety by a
hydrogen atom (Scheme 8). These reactions are vigorous
and require external cooling, especially at the beginning.
Both 24a and 24b can be purified by column chroma-
tography; however, distillation provides much better
2-Substituted tetrahydrofuran(pyran)-3-carboxalde-
hydes were previously difficult to access: the most
frequently used method for their preparation is a three-
step procedure based on (i) the preparations of either
2-(disubstituted)-4,7-dihydro-1,3-dioxepines or 2-(disub-
stituted)-5,6-dihydro-1,3-dioxocins, (ii) ruthenium hy-
dride-catalyzed isomerization of these cyclic compounds
(migration of double bond), and (iii) 1,3-alkyl migration
ring construction catalyzed by Lewis acids to give, after
hydrolysis of the intermediate acetal, the corresponding
aldehydes in ca. 20-30% overall yields.10,11,14,15
yields and comparable purity. Both the H and the 13C
1
NMR spectra of â-amino aldehyde ethyl acetals 24a ,b
contain characteristic sets of signals: in the proton NMR
there is a triplet at ca. 4.5-4.6 ppm assigned to the
proton of the acetal group, and no signals in the aromatic
region of the spectra, thus indicating a complete displace-
ment of the benzotriazolyl moiety by hydrogen. In the
carbon NMR there are no signals at low field responsible
for the carbon atom of amido group, but instead an extra
secondary carbon signal appears at high field (ca. 40-
60 ppm), corresponding to the carbon atom from the
reduced amido group.
(7) von der Bru¨ggen, U.; Lammers, R.; Mayr, H. J . Org. Chem. 1988,
53, 2920.
(8) Eckhardt, H.; Halbritter, K.; Rohr, W. Ger. Offen. DE 3,145,709;
Chem. Abstr. 1983, 99, 53734.
(9) Hoaglin, R. I.; Hirsh, D. H. J . Am. Chem. Soc. 1949, 71, 3468.
(10) Frauenrath, H.; Philipps, T. Tetrahedron 1986, 42, 1135.
(11) Frauenrath, H.; Sawicki, M. Tetrahedron Lett. 1990, 31, 649.
(12) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr. 1950, 1155.
(13) Brannock, K. C. J . Org. Chem. 1959, 24, 1382.
(14) Suzuki, H.; Yashima, H.; Hirose, T.; Takahashi, M.; Moro-oka,
Y.; Ikawa, T. Tetrahedron Lett. 1980, 21, 4927.

Syntheses of â-Alkoxyalkanal and â-Aminoalkanal Acetals
J . Org. Chem., Vol. 62, No. 3, 1997 703
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(Ben zo-
tr iazolyl)-1-alkoxy-3,3-dieth oxypr opan es (13a-c), 2-(Ben -
zot r ia zolyl)-3-(d iet h oxym et h yl)t et r a h yd r ofu r a n (16a ),
a n d 2-(Ben zotr ia zolyl)-3-(d ieth oxym eth yl)tetr a h yd r op y-
r a n (16b). A mixture of acetal 11 (6.75 mmol), alkyl vinyl
ether 12a -c or cycloalkyl vinyl ether 15a ,b (6.75 mmol), and
the corresponding Lewis acid catalyst (see below) was stirred
at rt for a time specified (see below). The residue was diluted
with diethyl ether, and the organic layer was successively
washed with NaOH (1 M solution in water) and then with
brine, separated, and dried over anhyd MgSO4. Evaporation
of the solvent in vacuo gave acetal 13 or 16 together with small
amounts of the ether 14 or 17. NMR assignments below are
given only for compounds 13 or 16.
â-Amino aldehydes are considered to be an important
building blocks in the biosynthesis and total synthesis
of various alkaloids, i.e., antitumor alkaloids Manzamine
A1 and Manzamine D216 and all Elaecarpus alkaloids.17
Most â-amino aldehydes are unstable and spontaneously
polymerize.16 Some examples of the Michael addition of
acrolein or related compounds to secondary amines which
resulted in the preparation of substituted â-amino alde-
hydes are described in the literature,16 but the stability
of these compounds was low and they had to be used
immediately after their preparation in solution. More
stable acetals of â-amino aldehydes were recently pre-
pared by the reaction of N-alkenyl-N,N-dialkylamines
with methanol catalyzed by CuCl2/LiPdCl4 in moderate
to good yields.18 We believe that the presently reported
preparation of â-amino-acetals holds great promise as
precursors of â-amino aldehydes and 1,3-amino-ethers
because of the easy manipulation and readily available
starting materials.
In summary, we found that the addition of (benzotria-
zol-1-yl)diethoxymethane 11 to various acyclic and cyclic
enol ethers and enamides produces the corresponding 1:1
adducts with no further additions observed. These
adducts can be easily modified by the reactions with
either NaAlH4 or with Grignard reagents, thus yielding
several classes of compounds which were previously
known but accessible only with difficulty: acyclic acetal-
ethers 18a -f, cyclic R-(substituted)-â-acetals 19a -c,
amino-acetals 24, and the corresponding 1,3-amino-
ethers of type 25.
1-(Ben zotr ia zolyl)-1,3,3-tr ieth oxyp r op a n e (13a ): cata-
lyst: p-TsOH (0.01 g), reaction time: 1 h; oil; yield 85% (based
1
on the NMR); H NMR δ 1.11-1.21 (m, 9 H), 2.43 (ddd, J )
14.0, 6.4 and 6.4 Hz, 1H), 2.63 (ddd, J )13.9, 7.4 and 5.2 Hz,
1H), 3.24-3.35 (m, 1H), 3.40-3.69 (m, 5H), 4.51 (dd, J ) 6.6
and 5.2 Hz, 1H), 6.21 (dd, J ) 7.4 and 6.1 Hz, 1H), 7.40 (t,
J ) 8.2 Hz, 1H), 7.49 (t, J ) 8.0 Hz, 1H), 7.77 (d, J ) 8.3 Hz,
1H), 8.08 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.3, 14.9, 38.6,
61.2, 61.5, 64.1, 87.0, 98.9, 110.6, 119.7, 123.8, 127.1, 131.2,
146.3.
1-(Be n zot r ia zolyl)-1-(isob u t yloxy)-3,3-d ie t h oxyp r o-
.
p a n e (13b): catalyst: BF3 Et2O (0.03 mL), reaction time: 20
1
h; oil; yield 88% (based on the NMR); H NMR δ 0.80 (d, J )
6.7 Hz, 3H), 0.84 (d, J ) 6.7 Hz, 3H), 1.16 (t, J ) 7.0 Hz, 3H),
1.19 (t, J ) 7.1 Hz, 3H), 1.81 (sextet, J ) 6.7 Hz, 1H), 2.37
-2.46 (m, 1H), 2.65 (ddd, J ) 14.0, 7.7 and 5.0 Hz, 1H), 2.97
(dd, J ) 8.9 and 6.7 Hz, 1H), 3.25 (dd, J ) 9.0 and 6.4 Hz,
1H), 3.40-3.54 (m, 2H), 3.56-3.70 (m, 2H), 4.55 (dd, J ) 6.7
and 5.1 Hz, 1H), 6.19 (dd, J ) 7.6 Hz and 5.9 Hz, 1H), 7.39 (t,
J ) 7.9 Hz, 1H), 7.49 (t, J ) 8.2 Hz, 1H), 7.77 (d, J ) 8.3 Hz,
1H), 8.09 (d, J ) 8.5 Hz, 1H); 13C NMR δ 15.0, 15.1, 18.9, 27.9
(2 C), 38.7, 61.4, 61.5, 75.4, 87.6, 99.0, 110.8, 119.8, 123.9,
127.2, 131.3, 146.4.
Exp er im en ta l Section
1-(Be n zot r ia zolyl)-1-(d od e cyloxy)-3,3-d ie t h oxyp r o-
p a n e (13c): catalyst: p-TsOH (0.01 g), reaction time: 2 h;
oil; yield 87% (based on the NMR); 1H NMR δ 0.80 (t, J ) 6.5
Hz, 3H), 1.08-1.17 (m, 24H), 1.36-1.47 (m, 2H), 2.35 (dt, J )
14.0 and 6.3 Hz, 1H), 2.56 (ddd, J ) 12.7, 7.6 and 5.2 Hz, 1H),
3.09-3.18 (m, 1H), 3.33-3.45 (m, 3H), 3.50-3.61 (m, 2H), 4.55
(dd, J ) 6.6 and 5.1 Hz, 1H), 6.12 (dd, J ) 7.5 and 6.2 Hz,
1H), 7.31 (t, J ) 7.1 Hz, 1H), 7.41 (t, J ) 7.2 Hz, 1H), 7.69 (d,
J ) 8.3 Hz, 1H), 8.00 (d, J ) 8.2 Hz, 1H); 13C NMR δ 14.0,
15.1, 15.2, 22.6, 25.8, 29.1, 29.2 (2 C), 29.4 (2 C), 29.5 (2 C),
31.8, 38.9, 61.5, 61.7, 69.0, 87.6, 99.2, 110.9, 120.0, 124.1, 127.3,
131.5, 146.7.
2-(Ben zot r ia zolyl)-3-(d iet h oxym et h yl)t et r a h yd r ofu -
r a n (16a ): catalyst: BF3‚Et2O (0.03 mL), reaction time: 1 h;
oil; yield 84% (based on the NMR); 1H NMR δ 1.12 (t, J ) 7.1
Hz, 3H), 1.18 (t, J ) 7.1 Hz, 3H), 2.07-2.20 (m, 1H), 2.42-
2.55 (m, 1H), 3.48-3.70 (m, 4H), 3.70-3.82 (m, 1H), 4.02-
4.22 (m, 2H), 4.62 (d, J ) 7.4 Hz, 1H), 6.43 (d, J ) 3.1 Hz,
1H), 7.35-7.40 (m, 1H), 7.47-7.52 (m, 1H), 7.69 (d, J ) 8.3
Hz, 1H), 8.06 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.7, 14.8, 26.9,
47.3, 61.2, 61.9, 68.8, 88.6, 102.3, 109.8, 119.4, 123.7, 127.1,
132.4, 145.8.
Gen er a l. See refs 19, 20. 1H NMR spectra were recorded
at 300 MHz, and 13C NMR spectra at 75 MHz in CDCl3. All
the compounds containing the benzotriazole moiety which are
described in the present paper consist of the mixture of
benzotriazol-1-yl (Bt1) and benzotriazol-2-yl (Bt2) isomers in
different ratios. Both isomers readily undergo the transforma-
tions described here, and therefore their isolation was not
performed. Experimental Section contains NMR data of the
mixtures of Bt1 and Bt2 isomers, without their complete
assignments.
(Ben zotr ia zol-1-yl)d ieth oxym eth a n e (11). A mixture of
benzotriazole (5.96 g, 50 mmol) and triethyl orthoformate (7.41
g, 50 mmol) was heated together with perfluorocarbon fluid
(3M Co. performance fluid, FC-84;21,22 ) (30 mL) in a round-
bottom flask fitted with a reversed Dean-Stark trap. After
20 h of reflux (during this time ethanol was collected in the
trap), the mixture was allowed to cool and ethyl acetate (40
mL) was added. The ethyl acetate layer was separated, the
solvent was evaporated in vacuo, and the residue was sub-
jected to fractional distillation, collecting the fraction with bp
95-97 °C/0.15-0.20 Torr. Colorless, viscous liquid; yield 86%;
1H NMR δ 1.25 (t, J ) 7.1 Hz, 6H), 3.54 (dq, J ) 9.4 and
7.1 Hz, 2H), 3.80 (dq, J ) 9.4 and 7.1 Hz, 2H), 6.79 (s, 1H),
7.40 (t, J ) 7.9 Hz, 1H), 7.50 (t, J ) 8.1 Hz, 1H), 7.92 (d, J )
8.3 Hz, 1H), 8.07 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.6, 63.1,
105.9, 112.2, 119.6, 124.4, 127.7, 130.8, 146.4. Anal. Calcd
for C11H15N3O2: C, 59.71; H, 6.83. Found: C, 59.36; H, 6.54.
er yth r o-2-(Ben zot r ia zol-1-yl)-3-(d iet h oxym et h yl)t et -
.
r a h yd r op yr a n (16b): catalyst: BF3 Et2O (0.03 mL), reaction
time: 24 h; oil; yield 82% (based on the NMR); 1H NMR δ 0.64
(t, J ) 7.0 Hz, 3H), 1.22 (t, J ) 7.0 Hz, 3H), 1.80-1.90 (m,
3H), 2.00-2.10 (m, 1H), 2.62-2.76 (m, 3H), 3.42-3.70 (m, 5H),
4.42 (d, J ) 8.0 Hz, 1H), 6.36 (d, J ) 4.2 Hz, 1H), 7.40 (t, J )
8.2 Hz, 1H), 7.52 (t, J ) 8.3 Hz, 1H), 7.64 (d, J ) 8.4 Hz, 1H),
8.08 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.6, 15.5, 20.9, 24.7,
42.9, 61.8, 63.1 (2C), 81.0, 103.5, 110.3, 119.7, 124.2, 127.5,
133.9, 145.1.
(15) Frauenrath, H.; Philipps, T. Liebigs Ann. Chem. 1985, 1951.
(16) Chesney, A.; Marko, I. E. Synth. Commun. 1990, 20, 3167.
(17) Chen, C.-K.; Hortmann, A. G.; Marzabadi, M. R. J . Am. Chem.
Soc. 1988, 110, 4829.
(18) Lai, J .-y.; Shi, X.-x.; Dai, L.-x. J . Org. Chem. 1992, 57, 3485.
(19) Katritzky, A. R.; Rachwal, B.; Rachwal, S.; Abboud, K. A. J .
Org. Chem. 1996, 61, 3117.
(20) Katritzky, A. R.; Xie, L. J . Org. Chem. 1995, 60, 3707.
(21) Zhu, D.-W. Synthesis 1993, 953.
(22) Katritzky, A. R.; Toader, D.; J iang, J . Org. Prep. Proced. Int.
1995, 27, 179.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(Su bsti-
tu ted )-1-a lk oxy-3,3-d ieth oxyp r op a n es (18a -f), 2-(Su b-
st it u t ed )-3-(d iet h oxym et h yl)t et r a h yd r ofu r a n s (19a ,b ),
a n d 2-Meth yl-3-(d ieth oxym eth yl)tetr a h yd r op yr a n (19c).
To a refluxing solution of the corresponding diethyl acetal
13a -c or 16a ,b (10 mmol) in toluene (50 mL) was added a
solution of the corresponding Grignard reagent RMgHlg,

704 J . Org. Chem., Vol. 62, No. 3, 1997
Katritzky et al.
prepared immediately prior to use from the appropriate alkyl,
aryl, or arylalkynylhalide (20 mmol) and magnesium turnings
(5.34 g, 22 mmol), in ether (50 mL) dropwise at such rate that
the ether distilled off and the temperature of the reaction
mixture was kept above 100 °C. After the addition was
completed, the mixture was refluxed for an additional time
(see below). The course of reaction was monitored by TLC and/
or NMR spectroscopy. After cooling to rt, the reaction mixture
was poured into ice-water mixture (200 mL), acidified by the
addition of acetic acid (5% solution in water), and extracted
with ether (50 mL). The ethereal solution was washed with
water, 5% Na2CO3, and again with water and dried over anhyd
MgSO4. Evaporation of the solvent in vacuo gave crude acetal
18 or 19 which was purified by column chromatography
(eluent, hexane:ether 4:1 for 18a ,b,d ,f, 19a ,b, or 8:1 for 18e
and 19c) or distilled (18c). Scale-up syntheses products can
be easily purified by distillation.
1-P h en yl-1,3,3-tr ieth oxyp r op a n e (18a ): reaction time:
0.5 h; oil; yield 70% (based on the NMR);23 isolated yield 52%;
bp 86-88 °C/2 Torr; 1H NMR δ 1.13-1.25 (m, 9H), 1.85-1.98
(m, 1H), 2.07-2.17 (m, 1H), 3.25-3.75 (m, 6H), 4.38 (dd, J )
9.0 and 5.0 Hz, 1H). 4.64-4.66 (m, 1H), 7.25-7.40 (m, 5H);
13C NMR δ 15.1, 15.2, 15.3, 42.3, 61.0, 61.2, 63.8, 78.3, 100.2,
126.4 (2 C), 127.3, 128.2 (2 C), 142.4. Anal. Calcd for
C15H24O3: C, 71.39; H, 9.59. Found: C, 71.45; H, 9.36.
1-P h en yl-3,5,5-tr ieth oxyp en t-1-yn e (18b): reaction time:
2 h; oil; yield 85% (based on the NMR); isolated yield 33%; 1H
NMR δ 1.20-1.28 (m, 9H), 2.03-2.12 (m, 1H), 2.20 (ddd, J )
13.7, 8.2 and 5.5 Hz, 1H), 3.46-3.61 (m, 3H), 3.64-3.76 (m,
2H), 3.83-3.93 (m, 1H), 4.39 (dd, J ) 8.0 and 6.1 Hz, 1H),
4.80 (dd, J ) 6.1 and 5.8 Hz, 1H), 7.27-7.40 (m, 3H), 7.42-
7.46 (m, 2H); 13C NMR δ 15.2, 15.4 (2 C), 40.2, 61.5, 61.7, 64.3,
66.6, 85.5, 88.2, 100.1, 122.8, 128.2 (3 C), 131.7 (2 C). Anal.
Calcd for C17H24O3: C, 73.88; H, 8.75. Found: C, 73.85; H,
8.78.
1,1-Dieth oxy-3-(d od ecyloxy)bu ta n e (18f): reaction time:
4 h; oil; yield 70% (based on the NMR); isolated yield 34%; 1H
NMR δ 0.88 (t, J )7.0 Hz, 3H), 1.13-1.26 (m, 27H), 1.48-
1.60 (m, 2H), 1.67 (ddd, J ) 13.9, 12.0 and 4.4 Hz, 1H), 1.82
(ddd, J ) 13.9, 8.9 and 4.0 Hz, 1H), 3.28 (dt, J ) 9.1 and 6.8
Hz, 1H), 3.47-3.55 (m, 4H), 3.58-3.72 (m, 2H), 4.67 (dd, J )
7.5 and 3.4 Hz, 1H); 13C NMR δ 14.1, 15.4 (2 C), 19.9, 22.7,
26.3, 29.4, 29.5, 26.6 (4 C), 30.2, 31.9, 41.4, 61.0, 61.7, 68.6,
72.0, 100.8; HRMS calcd for C20H42O3 330.3134 [M+], found
330.3042.
th r eo-2-P h en yl-3-(d iet h oxym et h yl)t et r a h yd r ofu r a n
(19a ): reaction time: 0.5 h; oil; yield 90% (based on the NMR);
1H NMR δ 1.13 (t, J ) 7.0 Hz, 3H), 1.21 (t, J ) 7.0 Hz, 3H),
1.91-2.16 (m, 2H), 2.49-2.58 (m, 1H), 3.42-3.58 (m, 3H),
3.60-3.75 (m, 1H), 3.91-3.98 (m, 1H), 4.04-4.12 (m, 1H), 4.51
(d, J ) 7.2 Hz, 1H), 4.82 (d, J ) 5.8 Hz, 1H), 7.21-7.40 (m,
5H); 13C NMR δ 15.0, 15.2, 28.2, 50.7, 61.4, 62.0, 68.0, 82.2,
103.7, 126.0 (2 C), 127.0, 128.1 (2 C), 143.1. This compound
was characterized as its DNP derivative 20 (see below).
th r eo-2-(1-Hexyn -1-yl)-3-(d ieth oxym eth yl)tetr a h yd r o-
fu r a n (19b): reaction time: 2.5 h; oil; yield 70% (based on
1
the NMR); isolated yield 25%; H NMR δ 0.89-0.94 (m, 6H),
1.20-1.25 (m, 7H), 1.35-1.55 (m, 4H), 1.75-1.95 (m, 1H),
2.05-2.15 (m, 1H), 2.19-2.26 (m, 2H), 2.61 (ddd, J ) 13.2,
7.9 and 5.3 Hz, 1H), 3.40-3.60 (m, 1H), 3.62-3.78 (m, 1H),
3.82-3.98 (m, 2H), 4.38 (d, J ) 7.4 Hz, 1H), 4.49-4.51 (m,
1H); 13C NMR δ 13.4, 15.1 (2 C), 18.3, 21.8, 27.5, 30.5, 50.0,
61.2, 61.5, 67.1, 70.1, 79.3, 85.3, 103.0. Anal. Calcd for
C15H26O3: C, 70.83; H, 10.30. Found: C, 70.83; H, 10.29.
2-Meth yl-3-(dieth oxym eth yl)tetr ah ydr opyr an (19c): re-
action time: 3 h; oil; yield 70% (based on the NMR); erythro-
isomer: yield 13% (after column chromatography, eluent:
hexane:ether 8:1); 1H NMR δ 1.17-1.25 (m, 9H), 1.40-1.55
(m, 1H), 1.57-1.68 (m, 3H), 1.98-2.06 (m, 1H), 3.43-3.80 (m,
6H), 3.92 (ddd, J ) 13.5, 6.9 and 3.9 Hz, 1H), 4.42 (d, J ) 8.7
Hz, 1 H); 13C NMR δ 15.3, 15.4, 20.0, 22.3, 24.4, 41.0, 60.6,
61.2, 63.3, 71.7, 102.5; HRMS calcd for C11H23O3 203.1647 [M+
+ 1], found 203.1651. Threo-isomer: yield 26% (after column
chromatography, eluent: hexane:ether 8:1); 1H NMR δ 1.20-
1.26 (m, 9H), 1.45-1.70 (m, 4H), 1.90-1.95 (m, 1H), 3.35-
3.55 (m, 4H), 3.60-3.80 (m, 2H), 3.87-3.98 (m, 1H), 4.37 (d,
J ) 3.0 Hz, 1H); 13C NMR δ NMR 15.1, 15.2, 19.9, 22.4, 25.8,
46.0, 63.3, 63.4, 67.6, 74.7, 103.8; HRMS calcd for C11H22O3
202.1569 [M+], found 202.1610.
1,1-Dieth oxy-3-(2-m eth ylp r op oxy)bu ta n e (18c): reaction
time: 0.5 h; oil; yield 72%; bp 61-63 °C/1.0-1.2 Torr; 1H NMR
δ 0.90 (d, J ) 6.6 Hz, 3H), 0.91 (d, J ) 6.7 Hz, 3H), 1.13 (d, J
) 6.2 Hz, 3H), 1.20 (t, J ) 7.1 Hz, 3H), 1.21 (t, J ) 7.1 Hz, H),
1.68 (ddd, J ) 14.0, 7.6 and 4.3 Hz, 1H), 1.75-1.87 (m, 2H),
3.03 (dd, J ) 8.9 and 7.0 Hz, 1H), 3.30 (dd, J ) 9.0 and 6.3
Hz, 1H), 3.45-3.74 (m, 5 H), 4.69 (dd, J ) 7.6 and 4.0 Hz,
1H); 13C NMR δ 15.3, 15.4, 19.4, 19.5, 19.8, 28.8, 41.5, 61.0,
61.7, 72.1, 75.5, 100.7; HRMS calcd for C12H27O3 219.1960 [M+
+ 1], found 219.1953.
2-P h en yl-1,2,3,4-tetr ah ydr ofu r an -3-car boxaldeh yde 2,4-
Din itr op h en ylh yd r a zon e (20). Acetal 19a (0.50 g, 2 mmol)
was dissolved in glacial acetic acid (15 mL), 2,4-dinitrophe-
nylhydrazine (0.59 g, 3 mmol) was added, and the mixture was
refluxed for 2 h. After cooling, the reaction mixture was
dissolved in water, neutralized with 5% Na2CO3, and extracted
with CHCl3 (2 × 20 mL). The combined organic extracts were
washed with water, dried over anhyd MgSO4, and the solvent
was evaporated in vacuo to give yellow solid which was
recrystallized from EtOH to give dark yellow plates; yield 72%;
mp 142-143 °C; 1H NMR δ 2.20-2.50 (m, 2H), 3.10-3.21 (m,
1H), 4.09-4.17 (m, 1H), 4.20-4.28 (m, 1H), 4.92 (d, J ) 7.5
Hz, 1H), 7.20-7.50 (m, 5H), 7.60 (d, J ) 5.8 Hz, 1H), 7.85 (d,
J ) 9.5 Hz, 1H), 8.27 (dd, J ) 9.5 and 2.5 Hz, 1H), 9.07 (d, J
) 2.6 Hz, 1H), 11.08 (br s, 1H); 13C NMR δ 31.0, 50.7, 68.1,
83.5, 116.5, 123.3, 125.9 (2 C), 127.9, 128.6 (2 C), 129.1, 129.9,
138.1, 140.6, 144.4, 150.6. Anal. Calcd for C17H15N4O5: C,
15.77; H, 57.46; N, 4.25. Found: C, 15.70; H, 57.13; N, 4.52.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Meth yl-
N-[1-(ben zotr ia zolyl)-3,3-d ieth oxyp r op yl]a ceta m id e (22a )
a n d 1-[1-(Ben zotr ia zolyl)-3,3-d ieth oxyp r op yl]p yr r olid in -
2-on e (22b). A mixture of acetal 11 (1.00 g, 4.5 mmol), 1-vinyl-
2-pyrrolidinone or N-methyl-N-vinylacetamide (4.5 mmol), and
BF3‚Et2O (0.03 mL) was stirred at 20 °C for 5 h. The reaction
mixture was diluted with ether (50 mL) and subsequently
washed with 1 M NaOH, brine, and water. Organic phase was
separated and dried over anhyd MgSO4. Solvent was evapo-
rated in vacuo to give colorless oil.
1-P h e n yl-3-(2-m e t h ylp r op oxy)-5,5-d ie t h oxyp e n t -1-
yn e (18d ): reaction time: 6 h; oil; yield 85% (based on the
NMR); isolated yield 37%; 1H NMR δ 0.94 (d, J ) 6.6 Hz, 3H),
0.96 (d, J ) 6.6 Hz, 3H), 1.23 (t, J ) 7.0 Hz, 3H), 1.24 (t, J )
7.1 Hz, 3H), 1.87-1.96 (m, 1H), 2.05-2.14 (m, 1H), 2.21 (ddd,
J ) 13.5, 8.5 and 5.2 Hz, 1H), 3.19 (dd, J ) 8.5 and 6.8 Hz,
1H), 3.50-3.62 (m, 3 H), 3.66-3.78 (m, 2 H), 4.37 (dd, J ) 8.2
and 5.8 Hz, 1H), 4.81 (dd, J ) 6.6 and 5.2 Hz, 1H), 7.29-7.33
(m, 3H), 7.41-7.46 (m, 2H); 13C NMR δ 15.3 (2 C), 19.4, 19.5,
28.5, 40.3, 61.5, 61.7, 66.9, 75.8, 85.4, 88.3, 100.1, 122.5, 128.2
(3 C), 131.7 (2 C). Anal. Calcd for C19H28O3: C, 74.96; H, 9.28.
Found: C, 75.38; H, 9.42.
1-(Dod ecyloxy)-1-p h en yl-3,3-d ieth oxyp r op a n e (18e): re-
action time: 1 h; oil; yield 70% (based on the NMR); isolated
1
yield 29%; H NMR δ 0.89 (t, J ) 6.9 Hz, 3H), 1.15-1.40 (m,
22H), 1.50-1.62 (m, 2H), 1.89 (ddd, J ) 13.9, 7.4 and 4.8 Hz,
1H), 2.11 (ddd, J ) 13.7, 9.1 and 4.4 Hz, 1H), 3.18-3.25 (m,
1H), 3.27-3.37 (m, 1H), 3.45-3.75 (m, 6H), 4.35 (dd, J ) 9.1
and 4.7 Hz, 1H), 4.65 (dd, J ) 7.4 and 4.4 Hz, 1H), 7.20-7.50
(m, 5H); 13C NMR δ 14.0, 15.3 (2 C), 22.6, 26.2, 29.3, 29.4,
29.6 (3 C), 29.8, 31.8, 42.5, 60.9, 61.0, 61.4, 68.7, 78.6, 100.3,
126.4 (2 C), 127.3, 128.2 (2 C), 142.6; HRMS calcd for C25H45O3
393.3369 [M+ + 1], found 393.3347.
(23) The “NMR yield” here and elsewhere indicates the percentage
yield based on the desired product contained in the crude reaction
mixture. This was calculated for compounds 13a -c, 16a ,b, 22a ,b as
the proportion of the 1H NMR signal integrals of the protons in the
R-position (to the benzotriazole moiety) of the intermediate to the
corresponding byproduct. For compounds 18a ,b,d -f, 19a -c a similar
calculations were used for acetal group proton signals in the desired
product and unreacted starting material.
N-Meth yl-N-[1-(ben zotr ia zolyl)-3,3-d ieth oxyp r op yl]a c-
eta m id e (22a ): oil; yield 90% (based on the NMR); 13C NMR
δ 15.0, 16.6, 21.9, 30.0, 34.9, 61.2, 62.3, 99.5, 110.6, 119.4,
124.2, 127.7, 132.7, 145.5, 171.1.

Syntheses of â-Alkoxyalkanal and â-Aminoalkanal Acetals
J . Org. Chem., Vol. 62, No. 3, 1997 705
1-[1-(Ben zotr ia zolyl)-3,3-d ieth oxyp r op yl]p yr r olid in -2-
on e (22b): oil isolated after synthesis solidified upon tritu-
ration with hexanes. White microcrystals; mp 79-81 °C; yield
N-[1-(3,3-Dieth oxyp r op yl)]p yr r olid in e (24b): oil; yield
92%; bp 65-68 °C/1 Torr; H NMR δ 1.21 (t, J )7.1 Hz, 6H),
1.76-1.82 (m, 4H), 1.83-1.90 (m, 2H), 2.45-2.55 (m, 6H),
3.46-3.56 (m, 2H), 3.61-3.71 (m, 2H), 4.59 (t, J ) 5.6 Hz, 1H);
13C NMR δ 15.3, 23.4, 33.1, 51.8, 54.2, 60.9, 101.6; HRMS calcd
for C11H24NO2 202.1807 [M+ + 1], found 202.1812.
1
1
70%; H NMR δ 1.11 (t, J ) 7.0 Hz, 3H), 1.19 (t, J ) 7.0 Hz,
3H), 1.78-1.95 (m, 1H), 1.95-2.11 (m, 1H), 2.28 (ddd, J ) 17.2,
9.6 and 6.4 Hz, 1H), 2.44 (ddd, J ) 17.2, 9.6 and 7.0 Hz, 1H),
2.68 (ddd, J ) 14.0, 6.9 and 6.9 Hz, 1H), 3.07 (ddd, J ) 14.0,
8.2 and 4.9 Hz, 1H), 3.20-3.37 (m, 2H), 3.45-3.71 (m, 4H),
4.38 (dd, J ) 6.6 and 4.9 Hz, 1H), 7.00 (dd, J ) 8.1 and 6.9
Hz, 1H), 7.35-7.43 (m, 1H), 7.52 (t, J ) 8.0 Hz, 1H), 7.83-
7.89 (m, 1H), 8.02-8.07 (m, 1H); 13C NMR δ 15.0, 15.1, 17.6,
30.6, 34.9, 42.3, 60.2, 61.4, 62.4, 99.3, 110.4, 119.3, 124.2, 127.7,
132.6, 145.4, 174.9. Anal. Calcd for C17H24N4O3: C, 61.43;
H, 7.28; N, 16.86. Found: C, 61.64; H, 7.22; N, 17.48.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Am in o-
Aceta ls (24a ,b). To a stirred under nitrogen solution of the
corresponding acetal 22a ,b (10 mmol) in dry THF (100 mL)
was added NaAlH4 (1.08 g, 20 mmol) in one portion. (CAU-
TION! A strong evolution of heat is observed; use external
cooling). The reaction mixture was stirred at rt for 1 h, and
20% NaOH was then added portionwise. A mixture was
stirred for 20 min and extracted with ether (3 × 50 mL). The
combined extracts were washed twice with 5% NaOH and then
with water and dried over anhyd MgSO4. The solvent was
evaporated in vacuo to yellow-orange oil. The crude product
was subjected to flash column chromatography (ethyl acetate)
and then to distillation.
Rea ction of Aceta l 24b w ith P h en ylm a gn esiu m Br o-
m id e. To a stirred solution of the acetal 24b (0.61 g, 3 mmol)
in toluene (50 mL) was added a solution of phenylmagnesium
bromide (9 mmol) in ether (6 mL) dropwise at reflux under
nitrogen. The course of the reaction was monitored by NMR.
After 5 h the reaction mixture was cooled to rt and poured
into water (200 mL), extracted with ether (2 × 50 mL), and
successively washed with brine and water. Organic phase was
separated and dried over anhyd MgSO4. The solvent was
evaporated in vacuo to give the oily residue. Column chro-
matography (ethyl acetate/MeOH, 9:1) afforded N-[1-(3-ethoxy-
3-phenylpropyl)]pyrrolidine (25); oil; yield 60%; 1H NMR δ 1.17
(t, J ) 7.0 Hz, 3H), 1.73-1.90 (m, 5H), 1.99-2.11 (m, 1H),
2.39-2.56 (m, 6H), 3.26-3.43 (m, 2H), 4.31 (dd, J ) 7.4 and
6.0 Hz, 1H), 7.23-7.36 (m, 5H); 13C NMR δ 15.2, 23.4, 37.6,
52.8, 54.1, 63.9, 80.4, 126.4 (2 C), 127.2, 128.2 (2 C), 142.9;
HRMS calcd for C15H24NO 234.1858 [M+ + 1], found 234.1857.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 18c, 18e, 18f, 19c, 24a , 24b, 25 (14
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
N-[1-(3,3-Dieth oxyp r op yl)]-N-eth ylm eth yla m in e (24a ):
oil; yield 82%; bp 42-45 °C/4 Torr; 1H NMR δ 1.09 (t, J ) 7.1
Hz, 3H), 1.22 (t, J ) 7.1 Hz, 6H), 1.80-1.87 (m, 2H), 2.26 (s,
3H), 2.44-2.51 (m, 4H), 3.47-3.57 (m, 2H), 3.62-3.72 (m, 2H),
4.58 (t, J ) 5.5 Hz, 1H); 13C NMR δ 12.0, 15.0, 31.2, 41.3, 51.1,
52.3, 60.7, 101.4; HRMS calcd for C10H24NO2 190.1807 [M++
1], found 190.1809.
J O9612335